Design, synthesis and evaluation of chiral nonracemic ligands and

DESIGN, SYNTHESIS AND EVALUATION OF CHIRAL NONRACEMIC LIGANDS AND

CATALYSTS FOR ASYMMETRIC SYNTHESIS

Michael P. A. Lyle Bachelor of Science, Simon Fraser University, 2000

THESIS SUBMITTTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

In the Department

of Chemistry

0 Michael P. A. Lyle 2005

SIMON FRASER UNIVERSITY

Summer 2005

All rights reserved. This work may not be reproduced in whole or in part, by photocopy

or other means, without permission of the author.

APPROVAL

Name:

Degree:

Title of Dissertation:

Michael P. A. Lyle

Doctor of Philosophy

Design, Synthesis and Evaluation of Chiral Nonracemic Ligands and Catalysts for Asymmetric Synthesis

Examining Committee:

Chair: Dr. Neil R. Branda Professor

Dr. Peter D. Wilson Assistant Professor, Senior Supervisor

Dr. Keith N. Slessor Professor Emeritus, Supervisory Committee

Dr. Vance E. Williams Assistant Professor, Supervisory Committee

Dr. Daniel B. Leznoff Associate Professor, Internal Examiner

Dr. Michael A. Kerr External Examiner Associate Professor Department of Chemistry, University of Western Ontario

Date Approved: Au.ausk t i ~ 0 0 s

DECLARATION OF PARTIAL COPYRIGHT LICENCE

The author, whose copyright is declared on the title page of this work, has granted to Simon Fraser University the right to lend this thesis, project or extended essay to users of the Simon Fraser University Library, and to make partial or single copies only for such users or in response to a request from the library of any other university, or other educational institution, on its own behalf or for one of its users.

The author has further granted permission to Simon Fraser University to keep or make a digital copy for use in its circulating collection, and, without changing the content, to translate the thesislproject or extended essays, if technically possible, to any medium or format for the purpose of preservation of the digital work.

The author has further agreed that permission for multiple copying of this work for scholarly purposes may be granted by either the author or the Dean of Graduate Studies.

It is understood that copying or publication of this work for financial gain shall not be allowed without the author's written permission.

Permission for public performance, or limited permission for private scholarly use, of any multimedia materials forming part of this work, may have been granted by the author. This information may be found on the separately catalogued multimedia material and in the signed Partial Copyright Licence.

The original Partial Copyright Licence attesting to these terms, and signed by this author, may be found in the original bound copy of this work, retained in the Simon Fraser University Archive.

Simon Fraser University Library Burnaby, BC, Canada

ABSTRACT

The work described in this thesis concerns the design, synthesis and evaluation of

new chiral nonracemic ligands and catalysts for use in asymmetric reactions.

A series of chiral nonracemic chloroacetals were prepared from 2-chloro-4-

methyl-6,7-dihydro-5H-[l]pyrindine-7-one and a variety of C2-symmetric and chiral

nonracemic 1,2-ethanediols (R = Me, i-Pr and Ph). These chloroacetals were further

elaborated, in a modular fashion, to provide a series of chiral ligands and catalysts.

A new class of C2-symmetric 2,2'-bipyridyl ligands were prepared in one step

fiom the chloroacetals via a nickel(0)-mediated homo-coupling reaction. These ligands

were then evaluated as chiral directors in copper@)-catalyzed asymmetric

cyclopropanation reactions of styrene and diazoesters (up to 44% ee).

A chiral pyridine N-oxide and a C2-symmetric 2,2'-bipyridyl N,N'-dioxide were

also prepared by direct oxidation of the corresponding pyridine and the 2,2'-bipyridine,

respectively. These chiral N-oxides were evaluated as chiral catalysts in

desymmeterization reactions of cis-stilbene oxide (up to 20% ee).

A series of pyridylphosphine ligands (P,N-ligands) were subsequently prepared in

two steps from the chloroacetals via a Suzuki coupling reaction with ortho-

fluorophenylboronic and on subsequent displacement of the fluoride with the potassium

anion of diphenylphosphine. These ligands were then evaluated in palladium-catalyzed

asymmetric allylic substitution reactions of racemic 3-acetoxy-l,3-diphenyl-1-propene

with dimethyl malonate. Optimization of the reaction conditions resulted in the

formation of the alkylated product in excellent yield (91%) and in high enantiomeric

excess (90%).

A related chiral nonracemic and C2-symmetric 2,2'-bipyridyl ligand was prepared

from 2-chloro-4-methyl-5H-[llpyrindine. This pyrindine was prepared from a common

intermediate that was used in the synthesis of the first generation of ligands. The

chirality of this second generation ligand was installed by a Sharpless asymmetric

dihydroxylation reaction (90% ee). The subsequently elaborated 2,2'-bipyridyl ligand

(enriched to >99% ee) was then evaluated in copper(1)-catalyzed asymmetric

cyclopropanation reactions of alkenes and diazoesters. In the case of the reaction of

para-fluorostyrene and tert-butyl diazoacetate, the corresponding cyclopropane was

formed in good diastereoselectivity (92:8) and in excellent enantioselectivity (99% ee).

This ligand was also evaluated in copper(I1)-catalyzed asymmetric Friedel-Crafts

alkylation reactions of various substituted indoles (up to 90% ee) and in copper(1)-

catalyzed asymmetric allylic oxidation reactions of cyclic alkenes with tert-butyl

peroxybenzoate (up to 9 1 % ee).

DEDICATION

For Litsa, my parents Robert and Heather, and my brother Eric.

ACKNOWLEDGEMENTS

I would like to thank my supervisor, mentor and friend Dr. Peter D. Wilson for his

support and guidance during the course of my doctoral studies. I am extremely grateful

for the training he has provided me with in synthetic organic chemistry.

The members of my supervisory committee, Dr. Keith N. Slessor and Dr. Vance

E. Williams are thanked for their helpful suggestions and encouragement throughout my

doctoral studies.

My past and present colleagues, Jeremy Pettigrew, Peggy Paduraru, Dr. Summon

Koul, Dr. Arun Narine, Dr. Jay Cadieux, Dr. Hongjuan Hu, Patrick Chen and Darren

McMurtrie are all thanked for their friendship as well as for many helpful and insightful

discussions.

For their technical assistance, Mrs. Marcy Tracey (NMR), Mr. Greg Owen (MS),

Mr. Phillip Ferreira (MS) and Mr. M. K. Yang (CHN microanalysis), are gratefully

acknowledged.

Mr. Neil D. Draper is thanked for performing all of the X-ray crystallography

described in this thesis. The results from these structure determinations were critical to

our research program.

Finally, the National Sciences and Engineering Research Council of Canada and

Simon Fraser University are thanked for financial support.

TABLE OF CONTENTS

APPROVAL

ABSTRACT

DEDICATION

ACKNOWLEDGEMENTS

TABLE OF CONTENTS

LIST OF SCHEMES

LIST OF FIGURES

LIST OF TABLES

LIST OF ABBREVIATIONS

CHAPTER 1: INTRODUCTION

DESIGN, SYNTHESIS AND EVAL UA TION OF CH IRA

AND CATALYSTS FOR ASYMMETRIC SWTHESIS

L NONRA CEMIC

General Overview

Asymmetric Synthesis

Strategies for Asymmetric Induction via Substrate, Auxiliary and

Reagent Control

Catalytic Asymmetric Hydrogenation and Oxidation

Reactions (Asymmetric C-H and C-0 Bond Formation)

Catalytic Asymmetric Carbon-Carbon Bond Formation Reactions

Asymmetric Organocatalysis

Chiral Cyclic Acetals in Asymmetric Synthesis

Proposed Studies

Chiral Nonracemic 2,2'-Bipyridyl Ligands: Syntheses and Reactions

2,2'-Bipyridines with Stereogenic Centres

1.9.2. 2,2 '-Bipyridines with Axial Chirality

1.9.3. 2,2'-Bipyridines with Planar Chirality

1.9.4. Catalytic Asymmetric Cyclopropanation Reactions

1.9.5. Catalytic Asymmetric Allylic Oxidation Reactions

1.10. Chiral2,2'-Bipyridine Mono- and bis-N-Oxides

I1

I11

v VI

VII

XVI

XXL

XXV

XXVII

LIGANDS

vii

1.11. Asymmetric Allylation and Aldol Reactions with 2,2'-Bipyridine

Mono- and bis-N-Oxides

1.12. Chiral Nonracemic Pyridylphosphine Ligands (Pa-Ligands)

1.12.1. Chiral Pyridylphosphine Ligands with Stereogenic Centres

1.12.2. Chiral Pyridylphosphine Ligands with Axial Chirality

1.12.3. Chiral Pyridylphosphine Ligands with Planar Chirality

1.12.4. Catalytic Asymmetric Allylic Substitution Reactions

1.12.5. Catalytic Asymmetric Heck Reaction

1.13. Thesis Overview

CHAPTER 2: RESULTS AND DISCUSSION

SYNTHESIS AND EVALUTION OF A SERIES OF NEW CHIRAL

NONRACEMlC C2-SYMMETRIC AND UNSYMMETRIC

2,2'-BIPYRIDYL LIGANDS

Introduction

Chiral Nonracemic 1,ZDiols (270a-c)

Synthesis of the Chloroketone (269)

Synthesis of the Chiral Nonracemic Cyclic Acetals (268a-c)

Synthesis of the Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl

Ligands [267a-c (R = Me, i-Pr and Ph)]

Synthesis of the Chiral Nonracemic Unsymmetric 2,2'-Bipyridyl

Ligands [271a (R = Me) and 271b (R = Ph)]

Evaluation of the C2-Symmetric 2,2'-Bipyridyl Ligands (267a-c) in

Copper(I)-Catalyzed Asymmetric Cyclopropanation Reactions of Styrene

and Diazoesters

Evaluation of the Unsymmetric 2,2'-Bipyridyl Ligands

[271a,b (R = Me and Ph)] in Copper@)-Catalyzed Asymmetric

Cyclopropanation Reactions of Styrene and Ethyl Diazoacetate 117

Optical Rotary Dispersion Spectrum of the Cu(267~)~*CuC12 Complex 118

2.10. Conclusions 120


SYNTHESIS AND EVALUATION OF NE W CHIRAL NONRACEMIC

PYRIDlNE N-OXIDES AND BIPYRIDINE N,N '-DIOXIDES

3.1. Introduction

3.2. Synthesis of the Chiral Nonracemic Pyridine N-Oxide (299)

3.3. Synthesis of the Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl

NJV-Dioxide (301)

3.4. Evaluation of the Chiral Nonracemic Pyridine N-Oxide (299)

and the C2-Symmetric 2,2'-Bipyridyl NJVr-Dioxide (301) in a

Catalytic Desymmeterization Reaction of cis-Stilbene Oxide

3.5. Conclusions


SYNTHESIS AND EVALUATION OF A SERIES OF NE W CHIRAL

NONRACEMC PYRIDYLPHOSPHINE LIGANDS

Introduction

Synthesis of the Chiral Nonracemic PJV-Ligands

[304a-c (R = Me, i-Pr and Ph)] from the Chiral Acetals (268a-c)

X-Ray Crystallographic Analysis of the Chiral PJV-Ligand [304c (R = Ph)]

Evaluation of the PJV-Ligands (304a-c) in Palladium-Catalyzed

Asymmetric Heck Reactions

Evaluation of the Pfl-Ligands (304a-c) in Palladium-Catalyzed

Asymmetric Allylic Substitution Reactions

Mechanistic Analysis of the Asymmetric Allylic Substitution Reaction

using the PJV-Ligand [304c (R = Ph)]

X-Ray Crystallographic Analysis of the Palladium(I1) Chloride Complex

of the PJV-Ligand [304a (R = Me)]

Attempted Application of the PJV-Ligands (304a-c) in Iridium-Catalyzed

Asymmetric Hydrogenation Reactions of Alkenes

Conclusions


SYNTHESIS AND EVALUATION OF A RELATED CHIRAL NONRA CEMIC

C2-SYMMETRIC 2,2 '-BIPYRID YL LIGAND

Introduction

Synthesis of the 2-Chloropyrindine (336)

Catalytic Asymmetric Dihydroxylation Reaction of the

2-Chloropyrindine (336)

Synthesis of the Chiral Nonracemic Cz-Symmetric 2,2'-Bipyridyl

Ligand [(+)-3331 from the Chloroacetal [(+)-3341

Synthesis of the Tetrahydroquinoline (344)

Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in Copperm-Catalyzed

Asymmetric Cyclopropanation Reactions of Alkenes

Asymmetric Copper(1I)-Catalyzed Friedel-Crafts Alkylation Reactions

Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in

Copper(I1)-Catalyzed Asymmetric Friedel-Crafts Alkylation Reactions

Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in Copperm-Catalyzed

Asymmetric Allylic Oxidation Reactions

Optical Rotary Dispersion Spectrum of the Copper(II) Chloride

[(+)-3331 Complex

Conclusions

CHAPTER 6: FUTURE WORK

6.1. Synthesis and Evaluation of New Chiral Nonracemic Cz-Symmetric

Tripyridine Ligands

6.2. Modification and Optimization of the Structural Features of the Chiral

Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligand [(+)-3331 and Evaluation in

Asymmetric Reactions

CHAPTER 7: GENERAL CONCLUSIONS

CHAPTER 8: EXPERIMENTAL SECTION

8.1. General Experimental Details

8.2. Experimental Procedures and Characterization Data Concerning Chapter 2

8.2.1. 4-MethyI-6,7-dihydro-5H-[l]pyrindine-2-01280

8.2.2. 2-Chloro-4-methyl-6,7-dihydro-5H-[l]pyrindine 281 206

8.2.3. 7(RS)-7-Acetoxy-2-chloro-4-methyl-6,7-dihy&o-5H-[l]pyrindine 282 207

8.2.4. 7(RS)-2-Chloro-4-methyl-6,7-dihydro-5H-[l]pindine-7-01283 208

8.2.5. 2-Chloro-4-methyl-6,7-dihy&o-5H-[l]pyrindine-7-one 269 209

8.2.6. 2-Chloro-4-methyl-6,7-dihy&o-5H-[l]pyrindine-7-one

(2R,3R)-2,3-Butanediol Acetal268a 2 10

8.2.7. 2-Chloro-4-methyl-6,7-dihydro-5H-[l]pyrindine-7-one

(1S72S)-1 ,2-Diisopropyl- l,2-ethanediol Acetal268b 21 1

8.2.8. 2-Chloro-4-methyl-6,7-dihydro-5H-[ l lpyrindine-7-one

(1S,2S)-1,2-Diphenyl- l,2-ethanediol Acetal268c 2 12

8.2.9. Preparation of 4,4'-Dirnethyl-6,6',7,7'-tetrahydro-SH,5'H-2,2'-

bi([l]pyrindinyl)-7,7'-dione (2R73R)-2,3-Butanediol bis-Acetal267a

and 4-Methyl-6,7-dihydro-5H-[l]pyrindjn-7-one (2R,3R)-2,3-Butanediol Acetal

286 from the 2-Chloropyridine 268a 213

8.2.10. 4,4'-Dimethyl-6,6',7,7'-tetrahy&o-5H,5'H-2,2'-bi([l]pyrindinyl)-

7,7'-dione (1S,2S)-1,2-Diisopropyl-1,2-ethanediol bis-Acetal267b 2 15

8.2.1 1. 4,4'-Dimethyl-6,6',7,7'-tetrahydro-5H,5'H-2,2'-bi([l]pyrindinyl)-

7,7'-dione (lS,2S)- 1,2-Diphenyl-l,2-ethanediol bis-Acetal267c 2 16

8.2.12. 2-Bromo-4-methyl-6,7-dihydro-5H-[l]pyrindine 287 217

8.2.13. (7RS)-7-Acetoxy-2-bromo-4-methyl-6,7-dihydro-5H-[l]pyrindine 288 2 18

8.2.14. (7RS)-2-Bromo-4-methyl-6,7-dihydro-5H-[l]pyrindin-7-ol289 219

8.2.15. 2-Bromo-4-methyl-6,7-dihydro-5H-[l]pyrindin-7-one 290 220

8.2.16. 2-Bromo-4-methyl-6,7-dihydro-5H-[l]pyrindin-7-one

(2R,3R)-2,3-butanediol acetal29la 22 1

8.2.17. Preparation of 4,4'-Dimethyl-6,6',7,7'-tetrahy&o-SH,5'H-2,2'-bi-

([l]pyrindinyl)-7,7'-dione (2R,3R)-Butanediol bis-Acetal267a

from the 2-Bromopyridine 291a 222

8.2.1 8. 4-Methyl-2-(2'-pyridyl)-6,7-dihydro-5H-[l]pyrindin-7-one

(2R,3R)-2,3-Butanediol Acetal271a 223

8.2.19. 4-Methyl-2-(2'-pyridyl)-6,7-dihydro-5H-[l]pyrindin-7-one

( lS,2S)-l,2-Diphenyl-l,2-ethanediol Acetal271b 224

8.2.20. General Procedure for the Copper(1)-Catalyzed Enantioselective

Cyclopropanation Reactions of Styrene 292 with the Ethyl and tert-Butyl

Esters of Diazoacetic Acid 293a,b 225

8.2.2 1. trans-2-Phenyl-cyclopropane-1 -carboxylic Acid Ethyl Ester 294a

8.2.22. trans-2-Phenyl-cyclopropane-1 -carboxylic Acid tert-Butyl Ester 294b

8.2.23. Procedure for the Preparation and Crystallization of

bis-[4,4'-Dimethyl-6,6',7,7'-tetrahydro-5H,5'H-2,2'-bi-

([l]pyrindinyl)-7,7'-dione (lS,2S)-l,2-Diphenyl-l,2-ethanediol

bis-Acetal] 26% Copper(1) Chloride Complex

8.2.24. X-Ray Crystallographic Analysis of the C~(267c)~CuCl~ Complex

8.2.25. Optical Rotary Dispersion Spectrum of the C~(267c)~CuCl~ Complex


8.3.1. 4-Methyl-6,7-dihydro-5H-[l]pyrindine-7-one (1 S,2S)-1,2-Diphenyl-

1,2-ethanediol Acetal300

8.3.2. 4-Methyl-6,7-dihydro-5H-[l]pyrindine-7-one (lS,2S)-1,2-Diphenyl-

1,2-ethanediol Acetal N-Oxide 299

8.3.3. 4,4'-Dimethyl-6,6',7,7'-tetrahydro-5H,5'H-2,2'-bi([l]pyrindinyl)-7,7'-dione

(lS,2S)-l,2-Diphenyl-l,2-ethanediol bis-Acetal N-Oxide 301

8.3.4. Asymmetric Synthesis of (lS,2S)-2-Chloro-1,2-diphenylethan-l-ol303


8.4.1. 2-(2-Fluorophenyl)-4-methyl-6,7-dihydro-5H-[l]pyrindine-7-one

(2R,3R)-2,3-Butanediol Acetal305a


(1S,2S)- 1,2-Diisopropyl- l,2-ethanediol Acetal305b


(lS,2S)-l,2-Diphenyl-l,2-ethanediol Acetal305c

8.4.4. 2-(2-Diphenylphosphanyl-phenyl)-4-methyl-6,7-dihydro-5H-[l]pyrindine-

7-one (2R,3R)-2,3-Butanediol Acetal304a


7-one (1 S,2S)- l,2-Diisopropyl- l,2-ethanediol Acetal304b


7-one (1 S,2S)- l,2-Diphenyl- l,2-ethanediol Acetal304c

8.4.7. Procedure for Palladium(0)-Catalyzed Asymmetric Heck Reactions:

Asymmetric Synthesis of (29-2,5-Dihydro-2-phenylfuran S-309

xii

8.4.8. General Procedures for Palladium(I1)-Catalyzed Asymmetric Allylic

Substitution Reactions: Asymmetric Synthesis of (1 R)-( l,3-Diphenylally1)-

malonic Acid Dimethyl Ester (11)-312 and (1S)-(1,3-Diphenylallyl)malonic

Acid Dimethyl Ester (S)-312

8.4.9. Crystallization of the Pa-Ligand 304c

8.4.10. X-Ray Crystallographic Analysis of the P,N-Ligand 304c

8.4.1 1. Procedure for the Preparation and Crystallization of the Palladium(I1)

Chloride P,N-Ligand 304a Complex

8.4.12. X-Ray Crystallographic Analysis of the Palladium(I1) Chloride

Pa-Ligand 304a Complex

8.4.13. 2-(2-Diphenylphosphanyl-phenyl)-4-methyl-6,7-dihydro-5H-

[ llpyrindine-7-one (2R,3R)-2,3-Butanediol Acetal Iridium(1)

Cyclooctadiene tetrakis[3,5-bis(Trifluoromethyl)phenyl]borate Complex 324a


[llpyrindine-7-one (1S,2S)-1,2-Diisopropylethanediol Acetal Iridium(1)

Cyclooctadiene tetrakis[3,5-bis(Trifluoromethyl)phenyl]borate Complex 324b


[ llpyrindine-7-one (lS,2S)-1,2-Diphenyl- 1,2-ethanediol Acetal Iridium(1)

Cyclooctadiene tetrakis[3,5-bis(Trifluoromethyl)phenyl]borate Complex 324c

Experimental Procedures and Characterization Data Concerning Chapter 5

2-Chloro-4-methyl-5H-[llpyrindine 336

(6S,7R)-2-Chloro-4-methyl-6,7-dihydro-5H-[l]pyrindine-6,7-diol

3-Pentanone Acetal (+)-334

(6S,6'S,7R,7'R)-4,4'-Dimethyl-6,6',7,7'-2,2'-bi-

([l]pyrindinyl)-6,6',7,7'-tetraol3-Pentanone bis-Acetal (+)-333

5,6,7,8-Tetrahydro-4-methylquinolin-2-ol347

2-Chloro-5,6,7,8-tetrahydro-4-methylquinoline 348

(8RS)-8-Acetoxy-2-chloro-5,6,7,8-tetrahydro-4-methylquinoline 349

2-Chloro-5,6-dihydro-4-methylquinoline 345

2-Chloro-5,6,7,8-tetrahydro-4-methyl-quinoline-7,8-diol 3-Pentanone Acetal344

General Procedure for Copper(1)-Catalyzed Enantioselective

Cyclopropanation Reactions of Alkenes 353a-e with Diazoesters 354a-c

(lR,2R)-trans-2-Phenyl-cyclopropane-I -carboxylic Acid Ethyl Ester 355a

... Xll l

8.5.1 1. (1 R,2R)-trans-2-Phenyl-cyclopropane- 1 -carboxylic Acid Benzyl Ester 355b

8.5.12. (1R,2R)-trans-2-Phenyl-cyclopropane-1 -carboxylic Acid tert-Butyl Ester 355c

and ent-355c

8.5.13. (1R,2R)-trans-2-(4-Methoxypheny1)-cyclopropane-1 -carboxylic Acid

tert-Butyl Ester 355d

8.5.14. (1R,2R)-trans-2-(4-Fluorophenyl)-cyclopropane-l-carboxylic Acid

tert-Butyl Ester 355e

8.5.15. (1 R,2R)-trans-2-(2'-Phenylethy1)-cyclopropane- 1 -carboxylic Acid

tert-Butyl Ester 355f

8.5.16. (1 R)-2,2-Diphenyl-cyclopropane-1-carboxylic Acid tert-Butyl Ester 3558

8.5.17. General Procedure for the Copper(I1)-Catalyzed Asymmetric Friedel-Crafts

Reactions using Ligand (+)-333

8.5.18. (2S)-3,3,3-Trifluoro-2-hydroxy-(indole-3-yl)-propionic Acid Ethyl Ester 369a

8.5.19. (2S)-3,3,3-Trifluoro-2-hydroxy-(indole-3-yl)-propionic Acid Methyl Ester 369b

8.5.20. (2S)-3,3,3-Trifluoro-2-hydroxy-(2-methylindole-3-yl)-propionic Acid

Methyl Ester 369c

8.5.2 1. (2S)-3,3,3-Trifluoro-2-hydroxy-(5-methoxyindole-3-yl)-propionic Acid

Methyl Ester 369d

8.5.22. (2S)-3,3,3-Trifluoro-2-hydroxy-(5-nitroindole-3-yl)-propionic Acid

Methyl Ester 369e

8.5.23. (29-3,3,3-Trifluoro-2-hydroxy-(1 -methylindole-3-y1)-propionic Acid

Methyl Ester 369f

8.5.24. (2S)-3,3,3-Trifluoro-2-hydroxy-(l -methyl-2-phenylindole-3-y1)-propionic

Acid Methyl Ester 3698

8.5.25. (4S)-4-(Indole-3-yl)-4-phenyl-2-oxo-butanoic Acid Methyl Ester 370

8.5.26. (2S,4R)-3,4-Dihydro-4-hydroxy-7-methoxy-2-phenyl-2H-chromene-4-methyl

Carboxylate 372

8.5.27. Procedure for the Preparation and Crystallization of the

CuClyLigand (+)-333 Complex

8.5.28. X-Ray Crystallographic Analysis of the CuClz.Ligand (+)-333 Complex

8.5.29. Optical Rotary Dispersion Spectrum of the CuC12.Ligand (+)-333 Complex

xiv

8.5.30 General Procedure for Copper(1)-Catalyzed Asymmetric Allylic Oxidation

Reactions of Cyclopentene 373a (n = l), Cyclohexene 373b (n = 2)

and Cycloheptene 373c (n = 3) with tert-Butyl Peroxybenzoate 374:

Asymmetric Syntheses of (15')-Cyclopent-2-enyl Benzoate S-375a (n = l),

(15')-Cyclohex-2-enyl Benzoate S-375b (n = 2) and

(IS)-Cyclohept-2-enyl Benzoate S-375c (n = 3) 317

8.5.3 1. (15')-Cyclopent-2-enyl Benzoate S-375a 318

8.5.32. (1S)-Cyclohex-2-enyl Benzoate S-375b 318

8.5.33. (15')-Cyclohept-2-enyl Benzoate S-375c 319

APPENDICES 320

9.1. Circular Dichroism Spectrum of the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex 320

9.2. Circular Dichroism Spectrum of the Copper(I1) Chloride.[(+)-3331 Complex 320

BIBLIOGRAPHY 322

LIST OF SCHEMES

Scheme 1.3.1.

Scheme 1.3.2.

Scheme 1.4.1.

Scheme 1.4.2.

Scheme

Scheme

Scheme 1.4.5.

Scheme 1.4.6.

Scheme 1.5.1.

Scheme 1.5.2.

Scheme 1.5.3.

Scheme 1.6.1.

Scheme 1.6.2.

Scheme 1.7.1.

Scheme 1.7.2.

Scheme 1.7.3.

Scheme 1.7.4.

The Diastereoselective Addition of Hydrogen Cyanide to D-Arabinose 3

The First Metal-Catalyzed Asymmetric Reaction: The Copper(1)-

Catalyzed Cyclopropanation Reaction of Styrene (1 966)

Asymmetric Hydrogenation Reaction of the N-Acetylaminoacrylic

Acid 19 using the Chiral C2-Symmetric Ligand DIOP 21 (1971)

The First Industrial Catalytic Asymmetric Process: The

Asymmetric Synthesis of L-DOPA 24 using the Chiral C2-Symmetric

Ligand DiPAMP 25 (1 974)

Asymmetric Synthesis of the Anti-Inflammatory Drug Naproxen using

the C2-Symmetric Chiral Ligand BINAP 28 (1987)

Sharpless-Katsuki Asymmetric Epoxidation of Allylic Alcohols using

C2-Symmetric Dialkyl Tartrates 31 as the Chiral Ligand (1 980)

The Asymmetric Synthesis of the Gypsy Moth Phermone

Disparlure 34 (198 1)

Sharpless Catalytic Asymmetric cis-Dihydroxylation of Alkenes

using C2-Symmetric biscinchona Alkaloid-Derived Chiral

Ligand 37 (1991)

Catalytic Asymmetric Cyclopropanation Reaction of Styrene using the

pseudo C2-Symmetric Chiral Semicorrin Copper(1) Complex 42 (1988)

Evans and Co-worker's Asymmetric Synthesis of the Key Intermediate

48 used in the Synthesis of ent-A'-~etrah~drocannabinol 47 (1997)

Trost and Co-worker's Palladium-Catalyzed Asymmetric Allylic

Substitution Reaction (1 994)

L-Proline-Catalyzed Asymmetric Intramolecular Aldol Reaction (1 974)

Chiral Arnine-Catalyzed Asymmetric Diels-Alder Reaction (2000)

Intramolecular Stereoselective Ring-Opening Reaction of the

Chiral Acetal67

A Chiral Cyclic Acetal as a Chiral Auxiliary for the Addition of

Grignard Reagents to Ketones

Diethylaluminum Chloride-Promoted Diels-Alder Reaction

Synthesis of the Chiral Tridentate Ligands 79 and 80

xvi

Scheme 1.9.1.

Scheme 1.9.2.

Scheme 1.9.3.

Scheme 1.9.4.

Scheme 1.9.5.

Scheme 1.9.6.

Scheme 1

Scheme 1

Scheme 1

Scheme 1.9.10.

Scheme 1.9.1 1.

Scheme 1.9.12.

Scheme 1.9.13.

Scheme 1.9.14.

Scheme 1.9.15.

Scheme 1.9.16.

Scheme 1.9.17.

Scheme 1.10.1.

Bolm and Co-worker's Chiral Nonracemic C2-Symmetric

2'2'-Bipyridyl Ligand 99 (1 990)

von Zelewsky and Co-Worker's Chiral Nonracemic [4,5]- and

[5,6]-Cycloalkeno-Fused 2,2'-Bipyridyl Ligands 104 and 105 (1992)

Katsuki and Co-Worker's Chiral Nonracemic C2-Symmetric

2'2'-Bipyridyl Ligands llOa,b (1992)

Katsuki and Co-Worker's Chiral Nonracemic C2-Symmetric

2'2'-Bipyridyl Ligand 113 (1994)

Katsuki and Co-Worker's Asymmetric Synthesis of the Chiral

Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligand 113 using a

Manganese(II1)-Catalyzed Asymmetric Epoxidation Reaction (1996)

Malkov and Co-worker's Pinene-Derived Chiral C2-Symmetric

2'2'-Bipyridyl Ligand 123 (PINDY) (2000)

Chelucci and Co-worker's Route to the Pinene-Derived Chiral

C2-Symmetric 2'2'-Bipyridyl Ligand 123 (2001)

Wong and Co-worker's Novel Axially Chiral2'2'-Bipyridyl

Ligand 136 (1990)

Botteghi and Co-Worker's Tartrate-Derived Axially Chiral

2,2'-Bipyridyl Ligand 140 (1 993)

Chan and Co-Worker's Axially Chiral2'2'-Bipyridyl Ligand

144 and 145 (2000)

Vijgtle and Co-Worker's Planar Chiral2'2'-Bipyridyl Ligand 153 (1999)

Fu and Co-worker's Novel Planar Chiral2'2'-Bipyridyl

Ligand 159 (2000)

Copper(1)-Catalyzed Asymmetric Cyclopropanation Reaction

of Alkenes

Industrial Synthesis of Cilastatin 166 using a Catalytic Asymmetric

Cyclopropanation Reaction

Copper(1)-Catalyzed Allylic Oxidation Reaction

Asymmetric Allylic Oxidation Reaction Catalyzed by the Chiral

Copper(1) Triflate bis(0xazoline) Complex 54

Synthesis of Leukotriene B4 190

Synthesis of Mono- and bis-N-Oxides of the Chiral Nonracemic

C2-Symmetric 2'2'-Bipyridyl Ligand 123 (2002)

3 8

3 9

40

4 1

43

44

46

48

49

50

52

5 3

54

5 5

60

62

62

64

xvii

Scheme 1.10.2.

Scheme 1.10.3.

Scheme 1.10.4.

Scheme 1.1 1.1.

Scheme 1.1 1.2.

Scheme 1.12.1.

Scheme 1.12.2.

Scheme 1.12.3.

Scheme 1.12.4.

Scheme 1.12.5.

Scheme 1.12.6.

Scheme 1.12.7.

Scheme 1.12.8.

Scheme 1.12.9.

Scheme 1.12.10.

Scheme 1.12.1 1.

Scheme 2.2.1.

Scheme 2.2.2.

Scheme 2.3.1.

Scheme 2.4.1.

Scheme 2.5.1.

Scheme 2.5.2.

Scheme 2.6.1.

Hayashi and Co-Worker's Novel Synthesis of the Axially Chiral

2,2'-Bipyridyl bis-N-Oxide 199 (2002) 66

Denmark and Co-Worker's Chiral Nonracemic C2-Symmetric

2'2'-Bipyridyl Ligand bis-N-Oxide 201 and 202 (2002) 67

Denmark and Co-Worker's Axially Chiral2,2'-Bipyridyl

bis-N-Oxides 208 (2002) 68

Catalytic Asymmetric Allylation Reactions of Aldehydes 69

Catalytic Asymmetric Addition Reactions of Silyl En01 Ethers to Ketones 70

Chelucci and Co-Worker's Chiral Pa-Ligand PYDIPHOS 222

derived from Tartaric Acid (1 996)

Katsuki and Co-Worker's Chiral Pa-Ligands 227a-f (1 999)

KoEovslj and Co-Worker's Terpene-Derived P,N-Ligand 232 (2002)

Chelucci and Co-Worker's Terpene-Derived P,N-Ligand 232 (2002)

Dai and Co-Worker's Axially Chiral Quinazolinone

Pa-Ligand 240 and 241 (1998)

Zhang and Co-Worker's Axially Chiral Pa-Ligand 243 (1 999)

Fu and Co-Worker's Planar Chiral P,N-Ligand 246 (2002)

Palladium-Catalyzed Allylic Substitution Reaction

Palladium-Catalyzed Asymmetric Allylic Substitution Reaction of

Racemic 1,3-Diphenylprop-2-enyl Acetate rac-253 with

Dimethyl Malonate 254

Palladium-Catalyzed Heck Reaction

Palladium-Catalyzed Asymmetric Heck Reaction

Preparation of the Chiral Nonracemic 1,2-Diol270c (R = Ph) via a

Sharpless Asymmetric Dihydroxylation Reaction

Synthesis of (lS'2S)- l,2-Diisopropyl- l,2-ethanediol270b

Synthesis of the Chloroketone 269

Synthesis of the Chiral Nonracemic Acetals 268a-c

Synthesis of the C2-Symmetric 2'2'-Bipyridyl Ligands 267a- c

Synthesis of the 2'2'-Bipyridyl Ligand 267a from the

2-Bromopyridine 29 1

Synthesis of the Unsymmetric 2,2'-Bipyridyl Ligands 271a

(R = Me) and 271b (R = Ph)

xviii

Scheme 2.8.1.

Scheme 2.10.1.

Scheme 3.2.1.

Scheme 3.3.1.

Scheme 3.4.1.

Scheme 4.2.1.

Scheme 4.6.1.

Scheme 4.6.2.

Scheme 4.8.1.

Scheme 4.8.2

Scheme 4.8.3.

Scheme 4.8.4.

Scheme 4.9.1.

Scheme 4.9.2.

Scheme 5.2.1.

Scheme 5.3.1.

Scheme 5.3.2.

Scheme 5.3.3.

Scheme 5.3.4.

Scheme 5.4.1.

Scheme 5.5.1.

Scheme 5.5.2.

Scheme 5.7.1.

Asymmetric Cyclopropanation Reactions using the Unsymmetric

2,2'-Bipyridyl Ligands 271a,b (R = Me and Ph)

Asymmetric Cyclopropanation Reaction of Styrene employing the

C2-Symmetric 2,2'-Bipyridine Ligand 267b (R = i-Pr)

Synthesis of the Chiral Nonracemic Pyridine-N-Oxide 299

Preparation of the Chiral Nonracemic C2-Symmetric

2,2'-Bipyridyl NJV-Dioxide 301

The Desymmeterization Reactions of cis-Stilbene oxide 302

Synthesis of the P,N-Ligands 304a-c (R = Me, i-Pr and Ph)

Preparation of (1,3-Diphenyl)allylpalladium Chloride Dimer 318

Synthesis of the Cationic n-Ally1 Palladium Complex 319

An Asymmetric Hydrogenation Reaction with the Chiral Iridium(1)

Phosphinooxazoline Complex 322

Synthesis of the Chiral Iridium(1)-Complexes 324a-c

Synthesis of the Asymmetric Hydrogenation Reaction Substrate 328

Synthesis of Methyl a-Acetamidocinnamate 332

Asymmetric Heck Reaction employing the Pa-ligand 304a (R = Me)

Asymmetric Allylic Substitution Reaction employing the P,N-ligand

304c (R = Ph)

Synthesis of the 2-Chloropyrindine 336

Sharpless Asymmetric Dihydroxylation Reaction of the Pyrindine 336

Modified Sharpless Asymmetric Dihydroxylation Reaction

Sharpless Asymmetric Dihydroxylation of Indene 337

Sharpless Asymmetric Dihydroxylation of an -8: 1 Mixture of the

Regioisomeric Pyrindines 336 and 337

Synthesis of the 2,2'-Bipyridyl Ligand (+)-333

Synthesis of the Dihydroquinoline 345 and its Sharpless

Asymmetric Dihydroxylation Reaction

The AD Reaction of Dihydronapthalene 351 with AD-mix$

Catalytic Asymmetric Friedel-Crafts Reactions of Activated

Aromatic Compounds Catalyzed by the Chiral Copper(I1)

bis(Oxazo1ine) Complex 363 (200 1)

xix

Scheme 5.7.2. Catalytic Enantioselective Michael Addition of Indoles to the

Q,y-Unsaturated a-Keto Ester 365 Catalyzed by the Chiral

Copper(I1) bis(Oxazo1ine) Complex 363 (2001)

Scheme 5.8.1. The Asymmetric Conjugate Addition Reaction of Indole 367a

to the P,y-Unsaturated a-Keto Ester 365

Scheme 5.8.2. The Conjugate Addition Reaction of 3-Methoxyphenol371

to the Q,y-Unsaturated a-Keto Ester 365

Scheme 5.9.1. Rationalization of the Stereochemical Outcome of the

Asymmetric Allylic Oxidation Reactions based on the Minimization

of Steric Interactions between the Catalyst and the Reacting Species 189

Scheme 5.1 1.1. Asymmetric Cyclopropanation Reaction employing the

C2-Symmetric 2,2'-Bipyridyl Ligand (+)-333 191

Scheme 5.1 1.2. Asymmetric Friedel-Crafts Reaction employing the


Scheme 5.1 1.3. Asymmetric Allylic Oxidation Reaction employing the


Figure 1.2.1.

Figure 1.2.2.

Figure 1.2.3.

Figure 1.3.1.

Figure 1.3.2.

Figure 1.3.3.

Figure 1.5.1.

Figure 1.5.2.

Figure 1 S.3.

Figure 1.6.1.

Figure 1.6.2.

Figure 1.7.1.

Figure 1.7.2.

Figure 1.8.1.

Figure 1.8.2.

Figure 1.8.3.

Figure 1.8.4.

Figure 1.8.5.

LIST OF FIGURES

The two mirror-image forms of a stereogenic tetrahedral carbon atom.

The highly toxic marine natural product palytoxin 1 which contains

sixty four stereogenic centres.

The structures of (R)-thalidomide (R)-2 and (9-thalidomide (59-2.

Application of Evans' oxazolidinone chiral auxiliary in an asymmetric

aldol reaction.

Asymmetric hydroboration/oxidation reaction of alkenes using chiral

borane reagent 14.

The general mechanistic principle of asymmetric catalysis.

Pseudo C2-symmetric chiral semincorrin ligands 38 (1988).

The C2-symmetric chiral bisoxazoline ligands 43-46 reported by Masamune

and Evans (1 990 and 199 1, respectively).

Evans and co-worker's retrosynthetic analysis of

ent-A'-tetrahydrocannabinol 47.

Bahmanyar and Houk's proposed transition state for the L-proline-catalyzed

asymmetric aldol reaction.

Diels-Alder reaction proceeds via the formation of a chiral iminium

ion 66 between the chiral amine catalyst 65 and the a$-unsaturated

aldehyde substrate 63.

General concept for the modular synthesis of structurally diverse chiral

auxiliaries, ligands and catalysts from the achiral ketones 72 and chiral

nonracemic C2-symmetric 1,2-diols 73.

7-Hydroxyindan-1 -one derived chiral auxiliaries 74.

Heterocyclic analogues 81 of the general design structure 71.

Retrosynthetic analysis of the new chiral nonracemic C2-symmetric

2,2'-bipyridyl ligands 82.

Retrosynthetic analysis of the chiral nonracemic unsymmetric

2,2'-bipyridyl ligands 84.

Retrosynthetic analysis of the chiral nonracemic pyridine N-oxides 86

and 87.

Retrosynthetic analysis of the chiral nonracemic pyridylphosphine ligands 88. 34

xxi

Figure 1.8.6. Retrosynthetic analysis of a related chiral nonracemic C2-symmetric

2,2'-bipyridyl ligand 91. 35

Figure 1.9.1. Mechanism of copper(1)-catalyzed cyclopropanation reactions of

alkenes with diazo compounds. 5 6

Figure 1.9.2. The relationship between diazo compound structure and reactivity (R = alkyl). 57

Figure 1.9.3. The contributing resonance structures of a metal carbene complex. 5 7

Figure 1.9.4. Mechanism for the copper@)-catalyzed asymmetric allylic oxidation reaction

of alkenes. 6 1

Figure 1.12.1. Mechanism for palladium-catalyzed allylic substitution reactions. 8 1

Figure 1.12.2. Dynamic conformational equilibria of cationic n-ally1 metal complexes. 8 1

Figure 1.12.3. Asymmetric Heck reactions reported by Shibasaki and co-workers and

Figure 2.1.1.

Figure 2.1.2.

Figure 2.2.1.

Figure 2.3.1.

Figure 2.5.1.

Figure 2.5.2.

Figure 2.5.3.

Figure 2.6.1.

Figure 2.6.2.

Figure 2.7.1.

Figure 2.7.2.

Figure 2.7.3.

Overman and co-workers (1989). 84

Retrosynthetic analysis of the chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligands 267a-c (R = Me, i-Pr and Ph).

Retrosynthetic analysis of the chiral nonracemic unsymmetric

2,2'-bipyridyl ligands 271a-c (R = Me, i-Pr and Ph).

Chiral nonracemic C2-symmetric 1,2-diols 270a-c.

Mechanism for the Boekekheide reaction used for the preparation of

the acetate 282. I H NMR spectra of the C2-symmetric 2,2'-bipyridyl ligands

267a-c (R = Me, i-Pr and Ph).

13c NMR spectra of the C2-symmetric 2,2'-bipyridyl ligands

267a-c (R = Me, i-Pr and Ph). 1 H NMR spectrum of the reductively dehalogenated product 286a. 1 H NMR spectra of the unsymmetric 2,2'-bipyridyl ligands

271a,b (R = Me and Ph).

13C NMR spectra of the unsymmetric 2,2'-bipyridyl ligands

271a,b (R = Me and Ph).

Rationalization of the stereochemical outcome of the AC reactions

based on the minimization of steric interactions between the

catalyst and the reacting species.

ORTEP representation of the C~(267c )~CuCl~ complex.

The proposed equilibrium established in solution of copper(1)

triflate and the 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr and Ph).

8 8

8 8

89

95

99

101

102

107

108

113

114

116

xxii

Figure 2.9.1.

Figure 3.1.1.

Figure 3.1.2.

Figure 3.2.1.

Figure 4.1.1.

Figure 4.2. I.

Figure 4.3.1.

Figure 4.5.1.

Figure 4.6.1.

Figure 4.6.2.

Figure 4.7.1.

Figure 5.1.1.

Figure 5.3.1.

Figure 5.3.2.

Figure 5.3.3.

Figure 5.4.1.

Figure 5.4.2.

Figure 5.4.3.

Figure 5.5.1.

Figure 5.6.1.

Optical rotary dispersion spectrum of the C~(267c )~CuCl~ complex. 119

Retrosynthetic analysis of the chiral pyridine N-oxide 299. 123

Retrosynthetic analysis of the chiral nonracemic C2-symmetric

2,2'-bipyridyl N,N'-dioxide 301. 124 1 H NMR spectrum of the chiral pyridine N-oxide 299. 125

Retrosynthetic analysis of chiral Pfl-Ligands 304a-c (R = Me, i-Pr and Ph). 130 1 H NMR spectra of the P,N-ligands 304a-c (R = Me, i-Pr and Ph). 133

ORTEP representation of the P,N-ligand 304c (R = Ph). 135

The nucleophilic species associated with each of the reagents used in the

AAS reactions. 139 31 P NMR spectrum of the cationic n-ally1 palladium complex 319. 143

Isomeric n-ally1 intermediates W- and M-320c and stereochemical

rationale [Nu = CH(COMe)2]. 144

ORTEP representation of the PdC12.P,N-ligand 304a complex. 147


2,2'-bipyridyl ligand 333. 155 I H NMR spectrum of the chiral chloroacetal (+)-334. 157

Diagnostic contacts observed in the NOESY spectrum of the

chloroacetal(+)-334. 158

The proposed transition state for the AD reaction of the 2-chloropyridine 336. 163 1 H NMR spectrum of the chiral nonracemic C2-symmetric

2,2 '-bipyridyl ligand (+)-333. 164 13 C NMR spectrum of the chiral nonracemic C2-symmetric

2,2 '-bipyridyl ligand (+)-333. 165

Enrichment of enantiomeric purity in the homo-coupling reaction

of the 2-chloroacetal(+)-334. 166

Retrosynthetic analysis of the 2,2'-bipyridine ligand 343. 166

Rationalization of the stereochemical outcome of the asymmetric

cyclopropanantion reactions based on the minimization of steric interactions

between the catalyst and the reacting species. 173

Figure 5.7.1. Possible strategies in the asymmetric Friedel-Crafts alkylation

reactions of activated aromatic compounds. 175

Figure 5.8.1. ORTEP representation of the CuCl2-ligand (+)-333 complex. 183

Figure 5.8.2. ORTEP representation of a CuCl2-tert-butyl bisoxazoline complex. 184

xxiii

Figure 5.8.3.

Figure 6.1.1.

Figure 6.2.1.

Figure 6.2.2.

Figure 6.2.3.

Figure 8.2.1.

Figure 8.2.2.

Figure 8.2.3.

Figure 8.4.1.

Figure 8.4.2.

Figure 8.5.1.

Figure 8.5.2.

Figure 9.1.1.

Figure 9.2.1.

Square-planar and tetrahedral coordination of the a-ketoester

substrates 368a,b and 365 to the chiral catalyst.

Retrosynthetic analysis of the chiral nomacernic C2-symmetric

tripyridine ligands 379a-c (R = Me, i-Pr and Ph).

Retrosynthetic analysis of the chiral pyridine N-oxide 382 and

NJV-dioxide 381.

Retrosynthetic analysis of the chiral nonracemic C?-symmetric

2,2'-bipyridyl ligands 383 (R' and R' = various substituents).


tripyridine ligands 396 (R' and R~ = various substituents).

ORTEP representation of the C~(267c)~.CuCl~ complex.

Partial ORTEP representation of the Cu(267~)~.CuC12 complex

showing the carbon atom numbering scheme of the 2,2'-bipyridyl ligand.

Optical rotary dispersion spectrum of the C~(267c )~CuCl~ complex.

ORTEP representation of the P,N-ligand 304c.

ORTEP representation of the PdC12.1igand 304a complex.

ORTEP representation of the CuC12-ligand (+)-333 complex.

Optical rotary dispersion spectrum of the CuC12.1igand (+)-333 complex.

Circular dichroism spectrum of the Cu(267~)~.CuC12 complex.

Circular dichroism spectrum of the CuC12.1igand (+)-333 complex.

xxiv

LIST OF TABLES

Table 2.7.1.

Table 4.4.1.

Table 4.5.1.

Table 5.6.1.

Table 5.8.1.

Table 5.9.1.

Table 8.2.1.

Table 8.2.2.

Table 8.2.3.

Table 8.2.4.

Table 8.4.1.

Table 8.4.2.

Table 8.4.3.

Table 8.4.4.

Table 8.4.5.

Table 8.4.6.

Table 8.4.7.

Table 8.4.8.

Table 8.5.1.

Table 8.5.2.

Table 8.5.3.

Table 8.5.4.

Asymmetric Cyclopropanation Reactions of Styrene 292 109

Palladium-Catalyzed Asymmetric Heck Reactions 136

Palladium-Catalyzed Asymmetric Allylic Substitution Reactions 138

Asymmetric Cyclopropanation Reactions of Alkenes 353a-e 170

Asymmetric Friedel-Crafts Alkylation Reactions of Indoles 367a-f 178

Asymmetric Allylic Oxidation Reactions 186

Summary of Crystallographic Data for the C~(267c )~CuCl~ Complex 23 1

Fractional Atomic Coordinates (A) and Equivalent Isotropic

Thermal Displacement Parameters [U(iso), (A2)] for the

C~(267c )~CuCl~ Complex 232

Bond Lengths (A) for the C~(267c )~CuCl~ Complex 236

Bond Angles (") for the Cu(267~)~-CuC12 Complex 238

Summary of Crystallographic Data for the P,N-ligand 304c 260


Thermal Displacement Parameters [U(iso), (A2)] for the P,N-Ligand 304c 261

Bond Lengths (A) for the P,N-Ligand 304c 263

Bond Angles (") for the P,N-Ligand 304c 265

Summary of Crystallographic Data for the

PdClyP,N-Ligand 304a Complex 270



PdC12.P,N-Ligand 304a Complex 27 1

Bond Lengths (A) for the Palladium(I1) Chloride PjV-Ligand 304a

Complex 274

Bond Angles (") for the PdC12.PjV-Ligand 304a Complex 275

Summary of Crystallographic Data for the CuC12.Ligand (+)-333

Complex 308



CuC12.Ligand (+)-333 Complex

Bond Lengths (A) for the CuC12.Ligand (+)-333 Complex

Bond Angles ( O ) for the CuClyLigand (+)-333 Complex

xxv

LIST OF ABBREVIATIONS

1D

13c NMR

'H NMR

a9.

Ac

acac

AAS

AC

AD

Anal.

Ar

BINAP

Bn

BSA

C

Calcd

CD

CI

COD

Conf.

COSY

CH2C12

CH3CN

CP*

d

D

dba

de

DET

dr

DMAP

degree(s)

one dimensional

carbon nuclear magnetic resonance

proton nuclear magnetic resonance

aqueous

acetate

acetoacetate

asymmetric allylic substitution

asymmetric cyclopropanation

asymmetric dihydroxylation

analytical

a v l

2,2'-bis(dipheny1phosphino)- 1,l '-binaphthyl

benzyl

N,O-bistrimethylsilylacetamide

concentration

calculated

circular dichroism

chemical ionization

1,5-cyclooctadiene

absolute configuration 1 H-'H correlation NMR spectroscopy

dichloromethane

acetonitrile

1,2,3,4,5-pentamethylcyclopentadienyl

distance

deuterium

dibenzylideneacetone

diastereoisomeric excess

diethyl tartrate

diastereoisomeric ratio

N,N-dimethyl-4-aminopyridine

DMSO

dppb

dppe

E

ee

El

ent

equiv

er

Et

ether

EtOAc

FAB

GC

h

HR

Hz

IR

J

L*

LUMO

M

MALDI-TOF

m-CPBA

Me

MeOH

min

mL

mol

MS

m/z

NCS

NMO

nOe

dimethylsulfoxide

1,4-bis(dipheny1phosphino)butane

1,5-bis(dipheny1phosphino)pentane

molar absorptivity

enantiomeric excess

electron impact

enantiomer

equivalent(s)

enantiomeric ratio

ethyl

diethyl ether

ethyl acetate

fast atom bombardment

gas chromatography

hour

high resolution

Hertz

infrared

coupling constant

chiral ligand

lowest unoccupied molecular orbital

molarity

matrix-assisted laser desorption ionization-time of flight

m-chloroperoxybenzoic acid

methyl

methanol

minute

milliliter

mole(s)

mass spectrometry

mass to charge ratio

N-chlorosuccinimide

N-methylmorpholine N-oxide

nuclear Overhauser effect

xxvii

NP

P I ORD

ORTEP

Ph

P K ~

p.s.i.

PPTS

rac

rt

TADDOL

TBS

temp

T f

TFPB

THF

THQ

TMS

p-TsOH

TS

UV

Vis

W

naphthyl

oxidation

optical rotary dispersion

Oakridge thermal ellipsoid plot

phenyl

acid dissociation constant

pounds per square inch

pyridiniump-toluenesulfonate

racernic

room temperature

a,a,a',a'-tetraaryl-2,2-dimethyl- 1,3-dioxolan-4,5-dimethanol

t-butyldimethylsilyl

temperature

trifluoromethane sulfonyl

tetrakis[2,6-bis(trifluoromethyl)phenyl]borate

tetrahydrofuran

tetrahydroquinoline

trimethylsilyl

p-toluenesulfonic acid

transition state

ultraviolet

visible

Watts

xxviii

CHAPTER 1: INTRODUCTION

DESIGN, SYNTHESIS AND E VAL UATlON OF CHIRAL NONRA CEMC LIGANDS AND CA TAL YSTS FOR

ASYMMETRIC SYNTHESIS

1.1. General Overview

The development of catalytic asymmetric synthesis is one of the major aspects of

modern synthetic organic chemistry. This thesis concerns the design, synthesis and

evaluation of new chiral nonracemic 2,2'-bipyridyl ligands (both Cz-symmetric and

unsyrnrnetric), pyridine N-oxides and pyridylphosphine ligands for use in catalytic

asymmetric reactions.

Ln the first section of this introductory chapter, a brief overview of the central

principles of asymmetric synthesis as well as the major achievements in this field are

discussed. Particular emphasis is placed on topics that relate to our original research

program. Following this general introduction, the design concepts and objectives of the

research discussed in this thesis are presented.

Chiral 2,2'-bipyridine ligands and Pfl-ligands have played an important role in

the field of asymmetric synthesis and so a detailed discussion of these classes of ligands,

including their syntheses and use in catalytic asymmetric reactions, is presented. This

discussion is provided in order to place the research results described in this thesis in

perspective.

1.2. Asymmetric Synthesis

In 1904, Marckwald defined asymmetric synthesis as "reactions which produce

optically active substances from symmetrically constituted compounds with the

intermediate use of optically active material but with the exclusion of all analytical

processes".1 The asymmetric synthesis of both natural and unnatural organic compounds

in chiral nonracemic form is a central challenge and objective in chemistry. As such, the

development of new chiral auxiliaries, reagents, ligands and catalysts for use in

asymmetric synthesis is at the forefront of chemical research.

Chirality is an intrinsic feature of all matter which cannot be superimposed on its

mirror image.2 The word chiral "handedness" is derived from the Greek word cheir,

which means hand. Our left and right hands are mirror images of each other and are not

superimposible, which is the minimum criterion for chirality.

The first evidence of molecular chirality came in 1848 when Louis Pasteur noted

the spontaneous crystallization of the sodium ammonium salt of racemic tartaric acid,

which is found in wine caskets, into enantiomorphic crystals.3 After careful physical

separation of the two types of crystals with tweezers, Pasteur made the discovery that

solutions of the crystals rotated plane polarized light in equal but opposite directions.

The only explanation for this observation was that the molecules in each of the crystals

were nonsuperimposable mirror images of one another.

(1) Marckwald, W. Asymmetric Synthesis. Ber. Dtsh. Chem. Ges. 1904,37, 1368.

(2) See, for example: (a) Gardner, M. In The New Ambidextrous Universe, 3rd ed., W . H. Freeman & Co.,

New York, 1990. (b) Heilbronner, E.; Dunitz, J. D. In Reflections on Symmetry, VHCA, Basel, 1993. (c)

Hoffmann, R. In The Same and Not the Same, Columbia University Press, New York, 1995.

(3) Pasteur, L. Ann. Chim. Phys. 1848,24,442.

In 1874, J. H. Van't Hoff and J. A. LeBel independently proposed the tetrahedral

arrangement of atoms around the central carbon atom in organic compounds. One of the

consequences of this tetrahedral arrangement is that when four different substituents are

attached to the central carbon, two mirror-image configurations of the central carbon are

possible and this stereogenic carbon atom (or molecule) is said to be chiid (Figure

1.2.1 .).

Mirror Plane

Figure 1.2.1. The two mirror-image forms of a stereogenic tetrahedral carbon atom.

There is a relationship between molecular chirality and living systems since many

of the molecules essential to life such as DNA, proteins and carbohydrates are composed

of chirul nonr-ucernic compounds (single enantiomerslmirror-image forms). Many

physiological responses are the result of highly specific interactions between these chiral

molecules. In Lewis Carroll's "Through the Looking Glass" which was published in

1872 and was a sequel to "Alice in Wonderland", Alice ponders "How would you like to

live in a looking-glass house, Kitty? 1 wonder if they'd give you milk in there'? Perhaps

looking-glass milk isn't good to drink". Alice was correct, if all the chiral molecules in

the milk, such as lactose, were present in their mirror image form then the milk would

"not be good to drink"

Since the seminal discoveries of Pasteur, Van't Hoff and LeBel in the mid-1 800's

organic chemists have been fascinated with chiral molecules and the creation of

molecular asymmetry. Natural products often contain amazingly intricate structures and

can be rich in stereochemical features. As an illustrative example, one of the most

complex natural products ever synthesized is the highly toxic marine natural product

palytoxin 1 which contains sixty four stereogenic centres (Figure 1.2.2.). This compound

could in principle exist as 264 = 1.8 x 1019 stereoisomers. In 1994, Kishi and co-workers

reported the total synthesis of one of the possible stereoisomers of palytoxin 1, the

naturally occurring stereoi~omer.~

Figure 1.2.2. The highly toxic marine natural product palytoxin I which contains sixty four

stereogenic centres.

(4) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W.-H.; Hawkins, L. D.;

Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W.; Mizuno, M.; Nakata, M.; Stutz, A. E.;

Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.; Uenishi, J.; White, J. B.; Yonaga, M. Total Synthesis

of Palytoxin Carboxylic Acid and Palytoxin Amide. J. Am. Chem. Soc. 1989, 111, 7530. (b) Suh, E. M.;

Kishi, Y. Synthesis of Palytoxin from Palytoxin Carboxylic Acid. J. Am. Chem. Soc. 1994, 116, 1 1205.

Asymmetric synthesis is very important to the pharmaceutical industry because

the structural differences between two enantiomeric drug molecules can have serious

consequences with respect to biological activity. A tragic example of this came with the

administration of racemic thalidomide to pregnant women in the 1960's. Unkonwn at the

time, (R)-thalidomide (R)-2 contained the desirable sedative properties while its

enantiomer (9-thalidomide (9-2, was a teratogen and induced fetal abnormalities

(Figure 1.2.3.).

I

Figure 1.2.3. The structures of (R)-thalidomide (R)-2 and (S)-thalidomide (S)-2.

The thalidomide tragedies increased awareness of the stereochemistry in the

action of drugs and as a result, the number of drugs administered as racemic compounds

has steadily decreased. In 2001, over 70% of the new chiral drugs approved were single

enanti~mers.~

1.3. Strategies for Asymmetric Induction via Substrate, Auxiliary and

Reagent Control

The strategies for the controlled formation of new stereogenic centres in

molecules may be grouped into three categories: (a) substrate-control; (b) auxiliary-

(5 ) Agranat, I . ; Caner, H.; Caldwell, J. Putting Chirality to Work: The Strategy of Chiral Switches. Nut.

Rev. Drug Discovery 2002,1,753.

control; and (c) reagent-control. In an asymmetric substrate-controlled reaction, an

existing stereogenic centre(s) in the reaction substrate directs the selective formation of

the new stereogenic centre during a reaction with an achiral reagent. Asymmetric

substrate-controlled reactions were the first type of asymmetric reactions to be conducted.

In 1894, Emil Fischer observed that the addition of hydrogen cyanide to D-arabinose 3

formed the mannononitriles 4 and 5 in a diastereoselective manner (66:34, respectively)

(Scheme 1.3.1

Scheme 1.3.1. The Diastereoselective Addition of Hydrogen Cyanide to DArabinose 3

OH OH HCN

OH OH OH OH

HO- - HO*H + HO+..,OH

OH H OH CN OH CN

Following Fischer's observations, progress was slow in gaining a deeper

understanding of asymmetric induction in substrate-controlled reactions. In 1952, Cram

and Abd Elhafez reported their studies on the stereochemistry of addition reactions to

aldehydes and ketones that contain a stereogenic centre adjacent to the carbonyl moiety.7

This study formed the basis for the now well-known concept of steric control of

asymmetric induction and the foundations were thus laid for the rational interpretation

and control of the stereochemical outcome of asymmetric substrate-controlled reactions.

A more recent approach to the asymmetric formation of new stereogenic centres

has involved the use of chiral auxiliaries. This method involves the temporary covalent

attachment of a chiral nonracemic compound (the chiral auxiliary) to the reaction

(6) Fischer, E. Dtsh. Chem. Ges. 1894,27, 3 189.

(7) Cram, D. J.; Abd Elhafez, F. A. Studies in Stereochemistry. The Rule of "Steric Control of Asymmetric

Induction" in the Syntheses of Acyclic Systems. J. Am. Chem. Soc. 1952, 74, 5828.

substrate. The temporary chiral environment imposed on the substrate by the chiral

auxiliary can then control the stereochemical outcome of a subsequent reaction with an

achiral substrate. In the final step of the three-step reaction sequence, the chiral auxiliary

is removed from the substrate to liberate the desired enantiomerically enriched product.

The auxiliary can then be recovered for use in additional asymmetric transformations.

For example, Evans' oxazolidinone-derived chiral auxiliaries have been used in

the asymmetric syn-aldol reaction of boron enolates (Figure 1.3.1 .).* In this reaction

sequence, the oxazolidinone auxiliary 6 was reacted with propionyl chloride 7 to afford

the N-acyl derivative 8 that was then converted to the corresponding (Z)-di-n-butylboron

enolate 8 upon treatment with di-n-butylboron triflate. The enolate 8 was then reacted

with acetaldehyde to form the syn-aldol addition product 10 via the "chair-like" transition

state 9 with high diastereoselectivity (>99% de). Of note, it is sometimes possible to

remove the minor diastereoisomeric impurity by recrystallization or chromatography at

this stage. In the final step, the desired enantiomerically enriched product 11 is removed

from the auxiliary by hydrolysis and the auxiliary 6 is recovered.

(8) Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective Aldol Condensations. 2. Erythro-selective Chiral

Aldol Condensations via Boron Enolates. J. Am. Chem. Soc. 1981,103,2127

Step 1: attach

substrate

1. propionyl chloride 7, NEt3 0 O B ( ~ - B U ) ~ 2. ( ~ - B U ) ~ B O T ~ A &,Me

'--i > 0 N

i - ~ r '+ i - ~ r 6 8

step 2: O 0B(n-Bu)2 RCHO,

perform 0 K N & ~ e -78 OC asymmetric 4 -

reaction b. I-Pr

0 OH step 3: Hydrolysis OH

cleave 0 N , R HO~C- * - R +

product Me Me i-Pr i-Pr

Figure 1.3.1. Application of Evans' oxazolidinone chiral auxiliary in an asymmetric aldol reaction.

The major drawback to the use of a chiral auxiliary is that it adds two extra steps

to a synthetic sequence (the attachment of the auxiliary to the substrate and the removal

of the auxiliary from the product). However, the use of a chiral auxiliary can serve

simultaneously to protect reactive functional groups during the asymmetric

transformation.

The use of chiral reagents in asymmetric reactions can be divided into two types:

(a) chiral compounds used in a stoichiometric quantity; and (b) chiral compounds used in

sub-stoichiometric quantities (chiral catalysts). In these types of asymmetric reactions,

the chirality of the reagent controls the stereochemical outcome of the reaction with a

prochiral or chiral substrate. For example, in 1951 Brown and co-workers reported the

chiral borane reagent diisopinocamphenylborane 14 which is readily synthesized by the

diastereoselective reaction of diborane with the chiral nonracemic natural product a-

pinene.9 This chiral reagent 14 has been shown to be effective in several reactions

including the asymmetric hydroboration/oxidation reaction of alkenes, such as (27-2-

butene 12, which affords the chiral alcohol 13 (Figure 1.3.2.).1•‹

I. 14, diglyme, 0 OC, 4 h 2. H202, diglyme, 90 OC, 4 h

13 (75% ee)

Figure 1.3.2. Asymmetric hydroboration/oxidation reaction of alkenes using the chiral borane

reagent 14.

The use of substoichiometric amounts of a chiral reagent to control the formation

of a new stereogenic centre(s) is referred to as a catalytic asymmetric process. Evidence

suggests that asymmetric reactions catalyzed by chiral molecules dates back to the

formation of key prebiotic building blocks such as carbohydrates. Chemists have

theorized that amino acids such as L-alanine and L-isovaline catalyzed enantioselective

condensation reactions between glycal and formaldehyde which afforded chiral

carbohydrate derivatives and resulted in the proliferation of chiral nonracemic molecules

in nature." In modem synthetic organic chemistry, the majority of chiral catalysts

(9) Brown, H. C.; Zweifel, G. A Stereospecific Double Bond Hydration of the Double Bond in Cyclic

Systems. J. Am. Chem. Soc. 1959,81,247.

(10) Verbit, L.; Heffron, P. J. Optically Active sec-Butylamine via Hydroboration. J. Org. Chem. 1967, 32,

3199.

(1 1) Pizzarello, S.; Weber, A. L. Prebiotic Amino Acids as Asymmetric Catalysts. Science 2004, 303,

1151.

developed have been transition metal complexes of chiral nonracemic organic ligands.

However, the use of chiral nonracemic organic compounds in catalytic asymmetric

synthesis "Organocatalysis" is a rapidly advancing technology.

In asymmetric transition metal-catalyzed reactions, the chirality of the complex is

transferred to the reaction product via the energy difference between all the possible

diastereoisomeric reaction transition states. The general mechanistic scheme shown

below involves three fundamental steps: ( 1 ) the coordination of reactants A and B to the

chiral transition metal complex (ML*); (2) the reaction of A and B to generate the chiral

reaction product (AB); and (3) the decomplexation of the reaction product from the chiral

transition metal complex (Figure 1.3.3.).

coordination @+@Y L'-L y

chiral catalyst

reaction \

' decomplexation

(R) or (S)-product

Figure 1.3.3. The general mechanistic principle of asymmetric catalysis.

In a landmark paper in 1966, Nozaki, Moriuti, Takaya and Noyori reported the

first example of the use of a chiral metal complex in asymmetric synthesis." The copper

(12) Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Asymmetric Induction in Carbenoid Reaction by

means of a Dissymctric Copper Chelate. Tetrahedron Lett. 1966,43,5239.

complex 18 of a chiral bidentate ligand, which was derived from salicylaldehyde and (R)-

a-phenylethylamine, was found to catalyze the reaction between styrene 16 and ethyl

diazoacetate 15 and form the diastereoisomeric trans-cyclopropane trans-17 and cis-

cyclopropane cis-17 in 6% and 10% enantiomeric excess, respectively (Scheme 1.3.2.).

Although the stereoselectivity of the reaction was low, the concept of using chiral

transition metal complexes in catalytic asymmetric synthesis had been established.

Scheme 1.3.2. The First Metal-Catalyzed Asymmetric Reaction: The Copper(1)-Catalyzed

Cyclopropanation Reaction of Styrene (1 966)

Reagents and conditions: (a) 1 mol % copper complex 18, CH2CI2, 58-60 "C, 72% (trans:cis =

70:30).

The following three sections of this chapter concern the major achievements in

catalytic asymmetric synthesis from 1966 to present day.

1.4. Catalytic Asymmetric Hydrogenation and Oxidation Reactions

(Asymmetric C-H and C-0 Bond Formation)

In 197 1, Dang and Kagan reported the synthesis of the C2-symmetric bidentate

diphosphine ligand DIOP 2 1 . ' ~ Their reason for choosing a C2-symmetric ligand with

(13) Dang, T. P.; Kagan, H. B. The Asymmetric Synthesis of Hydratropic Acid and Amino-Acids by

Homogenous Catalytic Hydrogenation. J. Chem. Soc., Chem. Commun. 1971,481.

two equivalent phosphorus donor atoms was to reduce the number of possible isomeric

metal complexes that could form with respect to an unsymmetrical ligand.I4 This can

have a beneficial effect on the stereoselectivity of a reaction by eliminating competing

and possibly less selective reaction pathways. In addition, the C2-symmetry of the ligand

can help to facilitate or simplify the interpretation of the results obtained in these

experiments. A complex formed between DIOP 21 and rhodium chloride cyclooctadiene

dimer was found to catalyze the asymmetric hydrogenation reaction of the N-

acetylaminoacrylic acid 19 and afford the D-phenylalanine derivative 20 in good

enantiomeric excess (72%) (Scheme 1.4.1 .). Notably, this was the first catalytic

asymmetric reaction to achieve relatively high levels of asymmetric induction.

Scheme 1.4.1. Asymmetric Hydrogenation Reaction of the N-Acetylaminoacrylic Acid 19 using

the Chiral C2-Symmetric Ligand DIOP 21 (1971)

0.20 mol % [RhCI(COD)I2, 0.20 mol % DIOP 21, H2,

NHCOMe Et0H:benzene (4:1), NHCOMe ~ h d room temperature

C02H + 95%

P ~ ~ C O ~ H

19 20 (72% ee)

The design principles that led Dang and Kagan to synthesize DIOP 21,

particularly that of the employment of an element of C2-symmetry, had a strong influence

on the course of further research in catalytic asymmetric synthesis.

In 1974 Knowles and co-workers reported that a rhodium(1) complex containing

the C2-symmetric bidentate diphosphine ligand DiPAMP 25 which contained two

(14) For a review on C2-symmetry, see: Whitesell, J. K. C2-Symmetry and Asymmetric Induction. Chem.

Rev. 1989,89, 1581.

stereogenic phosphorus atoms catalyzed highly enantioselective hydrogenation reactions

of unsaturated amides.15 Based on these results, Knowles and co-workers developed the

first industrial catalytic asymmetric process, a rhodium(1)-catalyzed asymmetric

hydrogenation reaction of the unsaturated amide 22 that afforded the phenylalanine

derivative 23, which is a key intermediate in the synthesis of L-DOPA 24 (Scheme

1 .4.2.).15

Scheme 1.4.2. The First Industrial Catalytic Asymmetric Process: The Asymmetric Synthesis of

L-DOPA 24 using the Chiral C2-Symmetric Ligand DiPAMP 25 (1974)

22 23 L-DOPA 24 ( 95% ee) DiPAMP 25

Reagents and conditions: (a) Rh[(DiPAMP 25)COD]BF4, H2, 1 00%; (b) H+/H~o.

In 1980, Noyori and co-workers reported the synthesis of the axially chiral C2-

symmetric bidentate diphosphine ligand BINAP 28.16 Both rhodium(1) and ruthenium(I1)

complexes of BINAP 28 were found to be remarkable catalysts for asymmetric

hydrogenation reactions of a wide range of alkene substrates. These hydrogenation

catalysts are currently used in the asymmetric syntheses of several chiral drugs. For

(15) Knowles, W. S. Asymmetric Hydrogenation. Acc. Chem. Res. 1983,16, 106.

(16) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. Synthesis of 2,2'-

bis(Dipheny1phosphino)-1,l'-binapthyl (BINAP), an Atropisomeric Chiral bis(Triaryl)phosphine, and its

use in the Rhodium(1)-Catalyzed Asymmetric Hydrogenation of Alpha-(acy1amino)acrylic acids. J. Am.

Chem. Soc. 1980,102,7932.

example, the anti-inflammatory drug naproxen 27 is prepared in high enantiomeric excess

(97%) from the a-arylacrylic acid 26 (Scheme 1.4.3.).17

Scheme 1.4.3. Asymmetric Synthesis of the Anti-Inflammatory Drug Naproxen using the C2-

Symmetric Chiral Ligand BlNAP 28 (1987)

0.5 mol % Ru(R-BINAP 28 ) (0A~)~ , H2, MeOH, room temperature

/ / 92%

\ JoZH OMe * $02H \ OMe

26 Naproxen 27 (97% ee)

In 1980, Sharpless and Katsuki reported a catalytic system for the asymmetric

epoxidation of allylic alcohols using titanium(1V) tetra-isopropoxide, a chiral C2-

symmetric dialkyl tartrate derivative 31 and tert-butyl hydroperoxide.'8 Using this

catalytic system, a wide array of allylic alcohol substrates 29 were oxidized in high

enantiomeric excess (>90%) (Scheme 1 .4.4.).19

(17) (a) Ohta, T.; Takaya, H.; Noyori, R. Asymmetric Hydrogenation of Unsaturated Carboxylic Acids

Catalyzed by BINAP-Ruthenium(I1) Complexes. J. Org. Chem. 1987, 52, 3174. (b) Kitamura, M.;

Yoshimura, M.; Tsukamoto, M.; Noyori, R. Synthesis of a-Amino Phosphonic Acids by Asymmetric

Hydrogenation. Enantiomer 1996, 1, 28 1.

(18) Katsuki, T.; Sharpless, K. B. The First Practical Method for Asymmetric Epoxidation. J. Am. Chem.

Soc. 1980,102,5974.

(19) For a review on the asymmetric epoxidation of allylic alcohols, see: Johnson, R. A.; Sharpless, K. B.

Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric S?/nthesis, 2nd ed.; Ojima,

I., Ed.; Wiley-VCH: New York, 2000, Chapter 6A.

Scheme 1.4.4. Sharpless-Katsuki Asymmetric Epoxidation of Allylic Alcohols using C2-

Symmetric Dialkyl Tartrates 31 as the Chiral Ligand (1 980)

Ti(Oi-Pr)4, dialkyl tartrate 31, - Since this initial report, the Sharpless-Katsuki protocol has been implemented

t-BuOH, CH2CI2, mol. sieves,

R A O H 0 "C to room temperature R- 01.. OH

industrially for the asymmetric synthesis of several important chiral molecules including

R02C C02R

(7R,8S)-disparlure 34, the pheromone of the gypsy moth (Figure 1 .4.5.).20

Scheme 1.4.5. The Asymmetric Synthesis of the Gypsy Moth Phermone Disparlure 34 (1981)

LMe b-d *

0 1 0

Reagents and conditions: (a) (-)-DET, Ti(0i-Pr),, t-BuOH, CH2CI2, 4 A mol. sieves, -40 "C, 4

days, 80%, 91% ee; (b) Cr03(pyridine)2, CH2CI2; (c) Ph3P(n-CloH21)Br, n-BuLi, THF; (d)

(Ph3P)3RhCI, HZ, benzene, room temperature, 24 h, 47% (over three steps).

Sharpless and co-workers made another important contribution to the field of

catalytic asymmetric synthesis in 199 1 when they reported the asymmetric cis-

dihydroxylation reaction of alkenes 35 using catalytic amounts of osmium tetraoxide and

a chiral C2-symmetric biscinchona alkaloid-derived ligand 37 in the presence of a

(20) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. Asymmetric Epoxidation Provides Shortest Routes to

Four Chiral Epoxy Alcohols which are Key Intermediates in Syntheses of Methymycin, Erythromycin,

Leukotriene C-1 and Disparlure. J. Am. Chem. Soc. 1981, 103, 464.

stoichiometric amount of a co-oxidant such as potassium ferricyanide(II1) or N-

methylmorpholine N-oxide (Scheme 1 .4.6.).21

Scheme 1.4.6. Sharpless Catalytic Asymmetric cis-Dihydroxylation of Alkenes using C2-

Symmetric biscinchona Alkaloid-Derived Chiral Ligand 37 (1991)

0.1 mol % 0s04, 0.5 mol % (DHQDhPHAL,

R&R K3Fe(CN)6, K2CO3, t-BuOH, H20

OH

35 36 (>go% ee)

OMe /

Me

OMe Me

(DHQDhPHAL 37

Of note, for their contributions to asymmetric synthesis, the Nobel Prize in

Chemistry for the year 2001 was awarded to K. Barry ~ h a r ~ l e s s ~ ~ for his work on the

asyrnmetric oxidation reactions of alkenes and to Ryoji ~ o ~ o r i ~ ~ and William S.

~ n o w l e s ~ ~ for their work on the asyrnmetric hydrogenation reactions of alkenes.

Until the mid-1980's, the majority of research in catalytic asyrnmetric synthesis

involved reactions which formed either carbon-hydrogen bonds (hydrogenation) or - -- -

(21) For a review on catalytic asymmetric dihydroxylation reactions, see: Kolb, H. C.; VanNieuwenhze, M.

S.; Sharpless, K. B. Catalytic Asymmetric Dihydroxylation. Chem Rev. 1994, 94, 2483.

(22) Sharpless, K. B. Searching for New Reactivity (Nobel Lecture). Angew. Chem., Znt. Ed. 2002, 41,

2024.

(23) Noyori, R. Asymmetric Catalysis: Science and Opportunities (Nobel Lecture). Angew. Chem., Znt. Ed.

2002,41,2008.

(24) Knowles, W. S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem., Znt. Ed. 2002, 41, 1998.

carbon-oxygen bonds (oxidation) which are commonly referred to as "atom-transfer

reactions". The next fiontier for development of catalytic asymmetric synthesis was and

continues to be the asymmetric construction of carbon-carbon bonds which is the focus of

the brief review in the following section.

1.5. Catalytic Asymmetric Carbon-Carbon Bond Formation Reactions

Inspired by the structures of natural corrinoid and porphinoid metal complexes,

which play a fundamental role in biocatalysis, Pfaltz and co-workers reported the

synthesis of a class of pseudo C2-symmetric bidentate dinitrogen ligands 38 that are

known as semi~orrins.~' The semicorrin ligands 38 were prepared from L-pyroglutamic

acid 39 which is commercially available (Figure 1.5.1 .).

P'

38 39

Figure 1.5.1. Pseudo C2-symmetric chiral semincorrin ligands 38 (1 988).

Pfaltz and co-workers first successful application of a chiral semmicorrin metal

complex was in the copper(1)-catalyzed asymmetric cyclopropanation reaction of styrene

16 and tert-butyl diazoacetate 40, the reaction that Nozaki, Moriuti, Takaya and Noyori

had reported over 30 years earlier. However, in this instance, the semicorrin ligand

(25) Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A. Synthesis of Chiral Semicomn Ligands and

General Concepts. Helv. Chim. Acta 1988, 71, 1541.

copper(1) t-butoxide complex 42 induced high levels of enantioselectivity (92-93% ee)

(Scheme 1.5.1.).'~

Scheme 1.5.1. Catalytic Asymmetric Cyclopropanation Reaction of Styrene using the pseudo

C2-Symmetric Chiral Semicorrin Copper(1) Complex 42 (1 988)

Reagents and conditions: (a) 1 mol % 42, CICH2CH2CI, room temperature, 65% (trans:cis =

81 :19).

The results of these cyclopropanation reactions confirmed the usefulness of the

semicorrin ligands in catalytic asymmetric carbon-carbon bond formation reactions and

formed the basis of a major area of research into the use of chiral bidentate dinitrogen

ligands in catalytic asymmetric reactions. In 1990 and 1991, Masamune and co-workers

reported the synthesis of the C2-symmetric bisoxazoline ligands 43, 44 and 45 while

Evans and co-workers reported the synthesis of the dimethyl substituted C2-symmetric

bisoxazoline ligands 46 (Figure 1.5.2.). 27,28,29

(26) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Enantioselective Cyclopropane Formation from Olefins with

Diazo Compounds Catalyzed by Chiral (Semicorrinato)copper Complexes. Helv. Chim. Acta. 1988, 71,

1553.

(27) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Asymmetric Catalytic Cyclopropanation of Olefins:

bis-Oxazoline Copper Complexes. Tetrahedron Lett. 1990, 31, 6005. (b) Lowenthal, R. E.; Masamune, S.

Asymmetric Copper-Catalyzed Cyclopropanation of Trisubstituted and Unsymmetrical cis-1,2-

Disubstituted Olefins: Modified bis-Oxazoline Ligands. Tetrahedron Lett. 1991,32, 7373.

Figure 1.5.2. The C2-symmetric chiral bisoxazoline ligands 43-46 reported by Masamune and

Evans (1 990 and 1991, respectively).

The use of chiral C2-symmetric bisoxazoline ligands has resulted in remarkarble

success in catalytic asymmetric synthesis in that exceptional levels of asymmetric

induction in a variety of reactions such as cyclopropanations, Diels-Alder cycloadditions,

ene reactions, aldol condensations, conjugate additions and Friedel-Crafts alkylations.30

These are important reactions in organic synthesis and these accomplishments have

greatly advanced the application of catalytic asymmetric synthesis in target-oriented

(28) Evans, D. A.; Woerpel, K. A.; Hinman, M. M. bis(Oxazo1ines) as Chiral Ligands in Metal-Catalyzed

Asymmetric Reactions. Catalytic Asymmetric Cyclopropanation of Olefins. J. Am. Chem. Soc. 1991, 113,

726.

(29) See also: Corey, E. J.; Imai, N.; Zhang, H.-Y. Designed Catalyst for Enantioselective Diels-Alder

Addition from a C2-Symmetric Chiral bis(Oxazo1ine)-Iron(II1) Complex. J. Am. Chem. Soc. 1991, 113,

729.

(30) For reviews on chiral semicorrin and bisoxazoline ligands, see: (a) Pfaltz, A. Chiral Sernicorrins and

Related Nitrogen Heterocycles as Ligands in Asymmetric Catalysis. Acc. Chem. Res. 1993, 26, 339. (b)

Johnson, J. S.; Evans, D. A. Chiral bis(oxazo1ine) Copper(I1) Complexes: Versatile Catalysts for

Enantioselective Cycloaddition, Aldol, Michael and Carbonyl Ene Reactions. Acc. Chem. Res. 2000, 33,

325.

synthesis.3' For example, in 1997 Evans and co-workers employed a bisoxazoline

copper(I1) complex to catalyze an asymmetric Diels-Alder reaction which was a key-step

in the enantioselective synthesis of ent-A'-tetrahydrocannabinol 47.32 Evans and co-

worker's retrosynthetic analysis of ent-A'-tetrahydrocannabinol 47 revealed that it could

be synthesized from the chiral nonracemic allylic alcohol 48 and olivetol 49 (Figure

1.5.3.).

Figure 1.5.3. Evans and co-worker's retrosynthetic analysis of ent-A'-tetrahydrocannabinol 47.

An enantioselective Diels-Alder reaction of the oxazolidinone 50 and (q -3-

methyl-buta- l,3-dienylacetate 51 catalyzed by the complex formed between 2 mol % of

the chiral bisoxazoline ligand 53 and 2 mol % of copper(I1) hexafluoroantimonate

afforded the allylic acetate 52 in high enantiomeric excess (98%). Treatment of this

compound with lithium benzoate followed by six equivalents of methyl magnesium

bromide afforded the required chiral nonracemic allylic alcohol 48 (Scheme 1.5.2.).

(3 1) Taylor, M. S.; Jacobsen, E. N. Asymmetric Catalysis in Complex Target Synthesis. Proc. Nut. Acad.

Sci. 2004, 101, 5368.

(32) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. Cationic bis(oxazoline)Cu(II) Lewis Acid Catalysts.

Applications to the Asymmetric Synthesis of ent-A'-~etrah~drocannabinol. Tetrahedron Lett. 1997, 38,

3193.

Scheme 1.5.2. Evans and Co-worker's Asymmetric Synthesis of the Key Intermediate 48 used in

the Synthesis of ent-A'-~etrah~drocannabinol 47 (1997)

52 (98% ee)

Reagents and conditions: (a) 2 mol % bisoxazoline ligand 53, 2 mol % Cu(SbF&, - 20 OC, 18 h,

57%; (b) LiOBn, THF, - 20 OC, 3 h, 82%; (c) MeMgBr (6.0 equiv), ether 0 OC, 2 h, 80%.

Trost and co-workers C2-symmetric bidentate diphosphine ligand 57 derived from

chiral nonracemic trans-l,2-diaminocyclohexane has been shown to be an excellent

ligand for palladium-catalyzed allylic substitution reactions. 33 An illustrative example is

the catalytic asymmetric allylic substitution reaction of racemic 3-acetoxycyclopentene

55 with the cesium anion of dimethyl malonate 54 which afforded the chiral cyclopentene

derivative 56 in excellent enantiomeric excess (98%) (Scheme 1 .5.3.).34

(33) For reviews on the palladium-catalyzed asymmetric allylic substitution reaction, see: (a) Trost, B. M.

Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org. Chem. 2004, 69, 5813. (b) Trost, B. M.

Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev. 1996,96, 395.

(34) Trost, B. M.; Bunt, R. C. Asymmetric Induction in Allylic Alkylations of 3-(Acyloxy)cyclopentenes.

J. Am. Chem. Soc. 1994,116,4089.

Scheme 1.5.3. Trost and Co-worker's Palladium-Catalyzed Asymmetric Allylic Substitution

Reaction (1 994)

Me02C,,C02Me

54 Me02C )---co~M~

+ [(C3H5)PdC1I2, Ligand 57, Cs2C03, CH2C12. rt 0

dAC 55

t

56 (98% ee)

1.6. Asymmetric Organocatalysis

One of the most exciting developments in the field of catalytic asymmetric

synthesis in recent years is "asymmetric organocatalysis" which concerns the acceleration

of an asymmetric chemical reaction with a substoichiometric amount of a chiral

nonracemic organic compound that does not contain a metal ion.35 Research in the field

of asymmetric organocatalysis has been driven by the problem of removal of traces of

metal contaminants from reaction products, the high costs of some transition metal

catalysts such as palladium and rhodium as well as the potential ability to use substrates

that contain unprotected functional groups such as alcohols and carboxylic acids in

catalytic asymmetric synthesis.

In 1974, Hajos and Parish demonstrated that L-proline 60 was a highly effective

catalyst for the intramolecular aldol reaction of the triketone 58 that afforded the bicyclic

product 59 in high enantiomeric excess (92%) (Scheme 1.6.1 .).36

(35) For reviews on asymmetric organocatalysis, see: (a) Dalko, P. I.; Moisan, L. In the Golden Age of

Organocatalysis. Angew. Chem., Int. Ed. 2004, 43, 5 138. (b) Special Issue: Asymmetric Organocatalysis.

Acc. Chem. Rex 2004,37, pp 487-63 1 .

(36) Hajos, Z. G.; Parrish, D. R. Asymmetric Synthesis of Bicyclic Intermediates of Natural Product

Chemistry. J. Org. Chem. 1974, 39, 161 5.

Scheme 1.6.1. L-Proline Catalyzed Asymmetric Intramolecular Aldol Reaction (1974)

0

tvle:3

3 mol % L-proline, CH3CN, room temperature, 6 days

+

100% O OH

L-Proline 60 58

59 (92% ee)

Bahmanyar and Houk have postulated, based upon computational studies, that L-

proline 60 acts as a bifunctional catalyst in intra- and intermolecular aldol condensation

reactions.37 In the proposed mechanism, L-proline 60 undergoes a condensation reaction

with the donor ketone 58 to afford the enamine 61 (Figure 1.6.1 .). The enamine 61 then

adds nucleophilically via a "chair-like" transition state 62 to the acceptor carbonyl which

is activated by the formation of an intramolecular hydrogen bond interaction with the

carboxylate moiety of L-proline.

Figure 1.6.1. Bahmanyar and Houk's proposed transition state for the L-proline-catalyzed

asymmetric aldol reaction.

Only recently has the potential of L-proline been more fully appreciated and it has

been used to catalyze a variety of asymmetric reactions with high enantioselectivities.

(37) (a) Cannizzaro, C. E.; Houk, K. N. Magnitudes and Chemical Consequences of R3N+-C-H...O=C

Hydrogen Bonding. J. Am. Chem. Soc. 2002, 124, 7163. (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.;

List, B. Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric

Intermolecular Aldol Reactions. .J, Am. Chem. Soc. 2003,125,2475.

These reactions include intra- and inter-molecular aldol reactions,38 Mannich reaction^;^

a-amination reactions4' and conjugate addition reaction^.^'

MacMillan and co-workers have recently developed a new strategy for

asymmetric organocatalysis based on the activation of a,B-unsaturated carbonyl

compounds via the reversible formation of iminium ions with a chiral nonracemic

secondary amine catalyst. For example, in the presence of 5 mol % of the chiral amine

65, the Diels-Alder reaction of cyclopentadiene and substituted a$-unsaturated aldehydes

63 afforded the cycloadducts exo-64 and endo-64 in high enantiomeric excess (84-93%)

(Scheme 1 .6.2.).42

(38) (a) Cordova, A.; Notz, W.; Barbas 111, C. F. Direct Organocatalytic Aldol Reactions in Buffered

Aqueous Media. Chem. Commun. 2002, 3024. (b) Cbrdova, A.; Notz, W.; Barbas 111, C. F. Proline-

Catalyzed One-Step Asymmetric Synthesis of 5-Hydroxy-(2E)-hexenal from Acetaldehyde. J. Org. Chem.

2002, 67, 301.

(39) Cordova, A. The Direct Catalytic Asymmetric Mannich Reaction. Acc. Chem. Res. 2004, 37, 102. (b)

List, B. The Direct Catalytic Asymmetric Three-Component Mannich Reaction. J. Am. Chem. Soc. 2000,

122, 9336. (c) List, B.; Pojarliev. P.; Biller, W. T.; Martin, H. J. The Proline-Catalyzed Direct Asymmetric

Three-Component Mannich Reaction: Scope, Optimization and Application to the Highly Enantioselective

Synthesis of 1,2-Aminoalcohols. J. Am. Chem. Soc. 2002, 124, 827.

(40) (a) List, B. Direct Catalytic Asymmetric a-Amination of Aldehydes. J. Am. Chem. Soc. 2002, 124,

5656. (b) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bsgevig, A.; Jsrgensen, K. A. Direct L-Proline

Catalyzed Asymmetric a-Amination of Ketones. J. Am. Chem. Soc. 2002,124,6254.

(41) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas 111, C. F. Amino Acid Catalyzed Direct Asymmetric Aldol

Reactions: A Bioorganic Approach to Catalytic Asymmetric Carbon-Carbon Bond Forming Reactions. J.

Am. Chem. Soc. 2001, 123, 5260. (b) Betancort, J. M.; Barbas 111, C. F. Catalytic Direct Asymmetric

Michael Reactions: Taming Naked Aldehyde Donors. Org. Lett. 2001,3, 3737.

(42) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New Strategies for Organic Synthesis: The First

Highly Enantioselective Organocatalytic Diels-Alder Reaction. J. Am. Chem. Soc. 2000, 122,4243.

Scheme 1.6.2. Chiral Amine-Catalyzed Asymmetric Diels-Alder Reaction (2000)

Q a

+ - arHo + QR CHO PI R AH exo-64 endo-64 65

63 exo:endo 1.3-1.0:l 84-93% ee

Reagents and conditions: (a) 5 mol % 65, MeOH/H20 (953, room temperature.

MacMillan and co-workers have postulated that the reaction proceeds via the

formation of a chiral iminium ion 66 between the chiral amine catalyst 65 and the a$-

unsaturated aldehyde substrate 63 that lowers the energy of the LUMO relative to that of

the achiral a$-unsaturated aldehyde (Figure 1.6.2.).

p N h t - ~ u Ph HCI

+ P kcBu P 0 - H 2 0

ph 3 + H 2 0

Figure 1.6.2. Diels-Alder reaction proceeds via the formation of a chiral iminium ion 66 between

the chiral amine catalyst 65 and the a,Sunsaturated aldehyde substrate 63.

MacMillan and co-workers have subsequently used their chiral amine catalyst 65

and related chiral amines to catalyze a variety of highly enantioselective asymmetric

reactions such as Friedel-Crafts alkylation reactions,13 Mukaiyama-Michael reaction^,"^

a-chlorination of aldehydes,15 and hydride reductions.16

(43) Paras, N. A.; MacMillan, D. W. C. New Strategies in Organic Catalysis: The First Asymmetric

Organocatalytic Friedel-Crafts Alkylation. J. Am. Chem. Soc. 2001, 123,4370.

1.7. Chiral Cyclic Acetals in Asymmetric Synthesis

We are currently involved in a research program that has concerned the design

and synthesis of novel chiral auxiliaries, ligands and catalysts that incorporate chiral

cyclic acetals as an element of chirality. This structural motif is the basis of the design

concept employed in the research project described in this thesis. In this section an

introduction to the use of chiral cyclic acetals in asymmetric synthesis is outlined.

Cyclic acetals can be formed by a simple acid-catalyzed condensation reaction of

an aldehyde or ketone with a 1,2- or 1,3-diol. The resultant acetals are stable under a

variety of reaction conditions and have thus found considerable use as common

protecting groups for carbonyl moieties.

More recently, chiral cyclic acetals have been applied in asymmetric synthesis for

the preparation of a variety of chiral nonracemic For example, in the

(44) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. The First Enantioselective Organocatalytic

Mukaiyama-Michael Reaction: A Direct Method for the Synthesis of Enantioenriched y-Butenolide

Architecture. J. Am. Chem. Soc. 2003, 125, 1192.

(45) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. The Direct Enantioselective Organocatalytic a-

Chlorination of Aldehydes. J. Am. Chem. Soc. 2004,126,4108.

(46) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. Enantioselective Organocatalytic Hydride

Reduction. J. Am. Chem. Soc. 2005,127,32.

(47) (a) AlibCs, R.; Busquk, F.; de March P.; Figueredo, M.; Font, J.; Gambino, M. E.; Keay, B. A. Acetals

of y-0x0-a&-unsaturated Esters in Nitrone Cycloadditions. Regio- and Stereo-chemical Implications.

Tetrahedron: Asymmetry 2001, 12, 1747. (b) Cossy J.; BouzBouz, S. A Short Access to (+)-Ptilocaulin.

Tetrahedron Lett. 1996, 37, 5091. (c) Alexakis, A.; Mangeney, P. Chiral Acetals in Asymmetric Synthesis.

Tetrahedron: Asymmetry 1990, 1,477.

(48) For reviews on the applications of two prominent classes of chiral acetals (Seebach's TADDOLs and

Ley's 1,2-diacetals) in asymmetric synthesis, see: (a) Seebach, D.; Beck, A. K.; Heckel, A. TADDOLs,

Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries. Angew. Chem., Int. Ed. 2001,

40, 92. (b) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, H. W. M.;

Reynolds, D. J. 1,2-Diacetals: A New Opportunity for Organic Synthesis. Chem. Rev. 2001, 101, 53.

presence of strong Lewis acids, the ring of chiral cyclic acetals can be opened with

nucleophiles. For instance, Johnson and co-workers have reported the intramolecular

cationic cyclization reaction of the chiral nonracemic acetal 67 in the presence of tin

tetrachloride which afforded the bicyclic compound 68 in good diastereoselectivity (85%

de) (Scheme 1.7.1 .).49

Scheme 1.7.1. Intramolecular Stereoselective Ring-Opening Reaction of the Chiral Acetal 67.

0 SnCI4, CH3N02, 0 "C, 1 min. +

0 0 63% me^" Me\'" OH

67 68 (85% de)

Chiral cyclic acetals have been installed in close proximity to prochiral centres to

direct subsequent substrate-controlled asymmetric reactions. For example, the addition

of Grignard reagents to the chiral cyclic acetal 69 afforded the chiral alcohols 70 in high

diastereoselectivity (>90% de) (Scheme 1 .7.2.).50

Scheme 1.7.2. A Chiral Cyclic Acetal as a Chiral Auxiliary for the Addition of Grignard Reagents

to Ketones

69 70 (>go% ee)

(49) Johnson, W. S. Biornimetic Polyene Cyclizations. Angew. Chem., Znt. Ed. 1976, 15, 9

(50) Tamura, Y.; Kondo, H.; Annoura, H.; Takeuchi, R.; Fujioka, F. Diastereoselective Nucleophilic

Addition to Chiral Open-Chain a-Ketoacetals: Synthesis of (R)- and (S)-Mevalolactone. Tetrahedron Lett.

1986,27,2117.

The relatively rigid nature of chiral cyclic acetals is a key feature in regard to their

use as chiral director^.^' The acetal subunit has the ability to restrict the conformational

flexibility within a substrate or reagent and thus can reduce the number of competing

diastereoisomeric transition states in an asymmetric reaction.

Our research program has involved the design and synthesis of novel chiral

auxiliaries, ligands and catalysts that incorporate cyclic acetals as chiral directors. The

general concept involves using the achiral parent ketones 72 and chiral nonracemic C2-

symmetric 1,2-diols 73 to synthesize, in a modular fashion, a structurally diverse series of

novel chiral auxiliaries, ligands and catalysts (Figure 1.7.1.).* The fused bicyclic acetals

71 incorporate a site (Z) at which a substrate could be attached in the case of a chiral

auxiliary or to which a metal could bind in the case of a chiral ligand as well as a reaction

site in the case of a chiral catalyst.

p p p p p -

(51) Mulzer, J.; Altenback, H.-J.; Braun, M.; Krohn, K.; Reissig, H.-U. In Organic Synthesis Ziighlights,

Wiley-VCH, Weinheim, 199 1, p 19.

(*) Modular: to be constructed with common units allowing flexibility and variety in use.

I atom or functional group to alter the electronic properties of the chiral reagent or

attachment site to a solid support I additional

binding site (i.e. N, P, 0 )

in a bi- or tridentate ligand

I chiral auxiliary: attachment site chiral reagent: complexation or catalytic site 1 variable substituents to alter

the steric and electronic environment of the chiral

auxiliary or reagent

Figure 1.7.1. General concept for the modular synthesis of structurally diverse chiral auxiliaries,

ligands and catalysts from the achiral ketones 72 and chiral nonracemic C2-symmetric 1,2-diols

73.

The use of C2-symmetric diols ensures that only a single diastereoisomer of the

acetals 71 is formed upon condensation. Moreover, one of the substituents (R) of the

orthogonally fused acetal moiety blocks one of the diastereotopic faces of these

molecules. The steric and electronic properties of the auxiliary or reagent could be varied

by condensing the ketone 72 with a variety of chiral nonracemic C2-symmetric 1,2-diols

73. The substituent (X) could also be modified to alter the electronic properties of these

potential chiral directors and thus enable the optimization of the structure for a particular

asymmetric reaction.

Narine and Wilson have demonstrated the potential of this concept by preparing

and evaluating a series of 7-hydroxyindan-1-one derived chiral auxiliaries 74 (Figure

1.7.2.) .~~ These structurally rigid chiral auxiliaries 74 [R = Me, i-Pr, Ph, CH20Me,

CH20Bn, CH20(1-Np)] were synthesized in a convergent manner from readily available

7-hydroxyindan-1 -one 75 and a series of corresponding chiral nonracemic C2-symmetric

1,2-diols 73.

Figure 1.7.2. 7-Hydroxyindan-1 -one derived chiral auxiliaries 74.

In the case of the acrylate derivative of the 7-hydroxyindan-1-one derived chiral

auxiliary 76 (R = i-Pr), a high degree of stereochemical induction was observed in a

diethylaluminum chloride-promoted Diels-Alder reaction with cyclopentadiene (dr =

91:9) (Scheme 1.7.3.).

Scheme 1.7.3. Diethylaluminum Chloride-Promoted Diels-Alder Reaction

Et2AICI (1.5 eq.), PhCH,, -78 "C

76 77 (91 :9 dr)

(52) Narine, A. A.; Wilson, P. D. Synthesis and Evaluation of 7-Hydroxyindan-1-one-Derived Chiral

Auxiliaries. Can J. Chem. 2005, 83,413.

Narine has also described the preparation of a series of related 7-hydroxyindan-l-

one derived chiral ligands 79 and These ligands were elaborated from the chiral

auxiliary 74 by ortho-formylation to afford the chiral salicylaldehyde 78 which was

subsequently condensed with 2-aminophenol or 1,l -diphenyl-2-aminoethanol to provide

the chiral tridentate ligands 79 and 80 (Scheme 1.7.4.). These ligands were evaluated in

vanadium(II1)-catalyzed asymmetric sulfur oxidation reactions. However, in this case,

low enantioselectivities were obtained.

Scheme 1.7.4. Synthesis of the Chiral Tridentate Ligands 79 and 80

Reagents and conditions: (a) 2-aminophenol, EtOH, room temperature, 18 h, 97% or 1,l-

diphenyl-2-aminoethanol, EtOH, room temperature, 18 h, 96%.

1.8. Proposed Studies

The goal of this research project was to synthesize heterocyclic analogues 81 of

the general structure 71 (Figure 1.8.1.). These analogues would then be further

elaborated to provide a structurally diverse group of chiral ligands and catalysts for

evaluation in catalytic asymmetric reactions. In this case, the analogues 81 contain a

nitrogen atom as a binding site for a transition metal. The substituent (X) could be

altered to tune the electronic properties of the ligand or catalyst. Alternatively, the

substituent could be selected to facilitate the synthesis of the target compounds. The

(53) Narine, A. A. Design, Synthesis and Evaluation of Chiral Auxiliaries, Ligands and Catalysts for

Asymmetric Synthesis. Ph. D. Thesis, Simon Fraser University, 2004.

chlorine atom, at C-2 (the position of the substituent, Y), could act as a reaction site for

further elaboration of these heterocyclic compounds to a series of ligands and catalysts.

Elaboration to a series of chiral - ligands and catalysts for use in catalytic asymmetric reactions

Figure 1.8.1. Heterocyclic analogues 81 of the general design structure 71.

Retrosynthetic analysis of a proposed new class of chiral nonracemic C2-

symmetric 2,2'-bipyridyl ligands 82 is shown below (Figure 1.8.2.). These ligands

should be available from the chiral nonracemic 2-chloropyridines 81 via a homo-coupling

reaction. The chiral2-chloropyridines 81 should in turn be available from the ketone 83

and a series of chiral nonracemic C2-symmetric 1,2-diols 73.

X

Figure 1.8.2. Retrosynthetic analysis of the new chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligands 82.

In a similar fashion, we proposed to synthesize and evaluate a series of

corresponding chiral nonracemic and unsymmeh-ic 2,2'-bipyridyl ligands 84. These

ligands would be available by coupling the chiral nonracemic 2-chloropyridines 81 with

the known 2-tri-n-butylstannylpyridine 85 (Figure 1 .8.3.).54

Figure 1.8.3. Retrosynthetic analysis of the chiral nonracernic unsyrnrnetric 2,2'-bipyridyl ligands

Furthermore, the chiral pyridine N-oxide 86 and the 2,2'-bipyridyl N,N-dioxide

87 could be synthesized by direct oxidation of the corresponding pyridines 71 and 2,2'-

bipyridines 82, respectively.

and and

Figure 1.8.4. Retrosynthetic analysis of the chiral nonracernic pyridine N-oxides 86 and 87

(54) McWhinnie, W. R.; Poller, R. C.; Thevarasa, M. An Inclusion Compound from Hexaphenylditin and

Tetraphenylditin. J. Organornet. Chem. 1968, 11, 499.

In order to further demonstrate the modular nature of our synthetic design, we

also proposed to synthesize and evaluate a series of chiral nonracemic pyridylphosphine

ligands 88. These Pa-ligands should be available from the 2-chloropyridines 81 via a

coupling reaction with ovtho-fluorophenylboronic acid 90 to afford the corresponding

fluorobiaryl compounds 89 followed by subsequent installation of the diphenylphosphino

moiety by the displacement of the fluoride atom with the anion of diphenylphosphine

(Figure 1.8.5.).

Figure 1.8.5. Retrosynthetic analysis of the chiral nonracemic pyridylphosphine ligands 88.

An alternative strategy based on a subtle structural modification of the chiral

cyclic acetal moiety was also considered. We proposed to synthesize and evaluate a

series of related chiral nonracemic C2-symmetric 2,2'-bipyridyl ligands 91. We

envisioned the synthesis of these 2,2'-bipyridyl ligands via an asymmetric

dihydroxylation reaction of the 2-chloropyrindine 94 followed by condensation of the

resultant diol 92 with a symmetrical ketone 93 (Figure 1.8.6.). The required 2-

chloropyrindine 94 could in principle be prepared from a common intermediate used in

the synthesis of the 2-chloroketone 83 (see: Scheme 1.8.2.). In contrast to the ligands and

catalysts described above which would require the synthesis of an achiral heterocyclic

ketone 83, this ligand would require the synthesis of the chiral nonracemic heterocyclic

diol92.

Figure 1.8.6. Retrosynthetic analysis of a related chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligand 91.

We considered that the chiral nonracemic Cz-symmetric 2,2'-bipyridyl ligands 82,

84 and 91 could offer some advantages over the chiral bisoxazoline ligands that have

been used successfully in many asymmetric transformations. In particular, the rigid

structure provided by the chiral cyclic acetal moiety would create a sterically "well-

defined" binding pocket around the transition metal centre. Moreover, we could make

structural modifications to the 2,2'-bipyndyl ligands by simply condensing the ketone 83

with a variety of chiral 1,2-diols 73 or conversely by condensing the chiral diol92 with a

variety of achiral ketones 93.

The following section concerns a brief literature review of the syntheses and

reactions of chiral nonracemic 2,2'-bip,yridyl ligands, pyridine N-oxides and

pyridylphosphine ligands that relate to the results of the research described in this thesis.

1.9. Chiral Nonracemic 2,2'-Bipyridyl Ligands: Syntheses and

Reactions

Of the many types of chiral ligands that have been developed for catalytic

asymmetric synthesis, chiral nonracemic 2,2',-bipyridines and 1,l O-phenanthrolines have

received considerable The 2,2'-bipyridine unit offers the potential for a

broad range of structural modifications that include the incorporation of stereogenic

centres as well as elements of planar and axial chirality. In addition, the electronic

properties of this type of ligand may be adjusted by appropriate functionalization of the

pyridine moieties. This class of bidentate ligands, as mentioned earlier, complements the

prominent class of chiral ligands, the bisoxazolines that have been employed with a great

degree of success in many asymmetric transformation^.^^

This section is divided into subsections that include brief reviews of 2,2'-

bipyridyl ligands with stereogenic centres, 2,2'-bipyridyl ligands with axial chirality and

2,2'-bipyridyl ligands with planar chirality. A review of the common reaction types that

these ligands have been employed in is also presented.

(55) (a) Malkov, A. V.; KoEovskY, P. Chiral Bipyridine Derivatives in Asymmetric Catalysis. Curr. Org.

Chem. 2003, 7, 1737. (b) Chelucci, G.; Thummel, R. P. Chiral2,2'-Bipyridines, 1,lO-Phenanthrolines, and

2,2':6',2"-Terpyridines: Synthesis and Applications in Asymmetric Homogenous Catalysis. Chem. Rev.

2002, 102, 3 129. (c) Fletcher, N. C. Chiral 2,2-Bipyridines: Ligands for Asymmetric Induction. J. Chem.

Soc., Perkin Trans. 1 2002, 183 1.

(56) (a) Reedijk, J. In Comprehensive Coordination Chemistry; Wilkinson, G., Gillard, R. D., McCleverty,

J. A., Eds; Pergamon Press: Oxford, 1987; Vol. 2, pp 73-98. (b) Kaes, C.; Katz, A.; Hosseini, M. W.

Bipyridine: The Most Widely Used Ligand. A Review of Molecules Containing at Least Two 2,2'-

Bipyridine Units. Chem. Rev. 2000, 100, 3553.

(57) For a recent review on chiral bisoxazolines in asymmetric transition metal catalyzed reactions, see for

example: Johnson, J. S.; Evans, D. A. Chiral bis(oxazo1ine) Copper(I1) Complexes: Versatile Catalysts for

Enantioselective Cycloaddition, Aldol, Michael and Carbonyl Ene Reactions. Acc. Chem. Res. 2000, 33,

325.

1.9.1. 2,2'-Bipyridines with Stereogenic Centres

In 1990, Bolm and co-workers reported the synthesis of the chiral nonracemic C2-

symmetric 2,2'-bipyridyl ligand 99 (Scheme 1.9.1 .).58 The synthesis of this ligand began

by monolithiation of 2,6-dibromopyridine 95 with n-butyllithium followed by

condensation with methyl 2,2-dimethylpropionate that afforded the ketone 96 in 80%

yield. Asymmetric reduction of the prochiral ketone 96 with (-)-b-

chlorodiisopinocamphenylborane afforded the chiral alcohol 97 in high enantiomeric

excess (90%). Following alkylation of the chiral alcohol 97 with methyl iodide, the

chiral2-bromopyridine 98 was subjected to a nickel(0)-mediated homo-coupling reaction

that afforded the desired C2-symmetric 2,2'-bipyridyl ligand 99 in 65% yield and in high

enantiomeric excess (>99%).

- - - -

(58) Bolm, C.; Zehnder, M.; Bur, D. Optically Active Bipyridines in Asymmetric Synthesis. Angew.

Chem., Int. Ed. 1990,29,205.

Scheme 1 .%I. Bolm and Co-worker's Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligand 99

Reagenfs and condifions: (a) n-BuLi, THF, -78 "C;

97 (90% ee)

99 (99% ee)

then f-BuC02CH3, -78 "C to room

temperature, 3 h 80%; (b) (-)-fi-chlorodiisopinocamphenylborane (1.2 equiv), neat, room

temperature, 2 days; then iminodiethanol (3.6 equiv), ether, 3 h, 59%; (c) NaH, CH31, THF, 0 "C

to rt, 1.5 h, 85%; (d) NiC12(H20)6 (1.2 equiv), Zn dust (1.3 equiv), PPh3 (4.8 equiv), DMF, 72 "C,

3.5 h, 65%.

In 1992, von Zelewsky and co-workers reported a general approach to chiral

nonracemic [4,5]- and [5,6]-cycloalkeno-fused 2,2'-bipyridyl ligands 104 and 105 that

involved ~ r o h n k e - t ~ ~ e ' ~ condensation reactions of 2-acetylpyridinepyridinium iodide

101 with the terpene-derived a$-unsaturated carbonyl compounds (-)-myrtenal 102 and

(+)-pinocarvone 103 in the presence of ammonium acetate which afforded the chiral

nonracemic 2,2'-bipyridyl ligands 104 and 105, respectively (Scheme 1 .9.2.).60

(59) Krohnke, F. Neuere Methoden der Praparativen Organischen Chemie Synthesen mit hilfe von

Pyridiniumsalzen. Angew. Chem., Int. Ed. 1963,2, 386.

(60) Hayoz, P.; von Zelewsky, A. New Versatile Optically Active Bipyridines as Building Blocks for

Helicating and Caging Ligands. Tetrahedron Lett. 1992,33,5 165.

Scheme 1.9.2. von Zelewsky and Co-worker's Chiral Nonracemic [4,5]- and [5,6]-Cycloalkeno-

Fused 2,2'-Bipyridyl Ligands 104 and 105 (1 992)

Reagenfs and conditions: (a) 12, pyridine; (b) NH40Ac, formamide, 100 "C, 12 h, 55% (c)

NH40Ac, formamide, 70 "C, 6 h, 75%.

Beginning in 1992, Katsuki and co-workers published a series of papers that

described the syntheses of a number of chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligands that contained [5,6]-cycloalkeno-fused bipyridine units with stereogenic centres

at the a,aJ-positions of the fused rings. In the first paper, they reported the syntheses of

the a,al-dimethyl substituted bipyridine ligands llOa,b (Scheme 1.9.3.).~' The syntheses

began from the commercially available 2-chloropyridines 106a,b that were deprotonated

with lithium N,N-diisopropylamide and the resultant anions were subsequently condensed

with (-)-menthy1 chloroformate to afford the carbonates 107a,b as mixtures of

diastereoisomers. The more polar compound of each of the pairs of diastereoisomers,

that had (8-configuration at the newly established stereogenic centre, were isolated by

(61) Ito, K.; Tabuchi, S.; Katsuki, T. Synthesis of New Chiral Bipyridine Ligands and Their Application to

Asymmetric Cyclopropanation. Synlett 1992, 575.

flash chromatography and then converted to the tosylates 108a,b by reduction with alane

followed by treatment with tosyl chloride. The tosylates 108a,b were then reduced with

lithium triethylborohydride to afford the 2-chloropyridines 109a,b. These compounds

were then subjected to a nickel(0)-mediated homo-coupling reaction that afforded the

chiral nonracemic C2-symmetric 2,2'-bipyridyl ligands llOa,b.

Scheme 1.9.3. Katsuki and Co-worker's Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligands

lire lire ~6

Reagents and conditions: (a) LDA, (-)-menthy1 ch loroformate, -78 "C, then chromatographic

separation of the diastereoisomers, 43% (107a), 37% (107b); (b) AIH3, THF; (c) TsCI, NEt3,

DMAP (cat.); (d) LiBEt3H, THF; (e) NiC12(H20)6, Zn dust, PPh3, DMF, 47% (over four steps)

(1 1 Oa), 33% (over four steps) (1 1 Ob).

Katsuki and co-workers subsequently reported the synthesis of a related 2,2'-

bipyridine ligand 113 that contained larger substituents than methyl groups at the a and

a' positions (Scheme 1.9 .4 . ) .~~ The starting material was again the commercially

available 2-chloropyridine 106a which was deprotonated regioselectively with lithium

Nfl-diisopropylamide and the resultant anion was reacted with acetone to afford the

racemic tertiary alcohol 11 1 which was then resolved by preparative chiral HPLC (Daicel

Chiracel OF column). The tertiary alcohol that eluted first from the chiral column, which

had (S) stereochemistry, was then reacted with tert-butyldimethylsilyl triflate. The

resultant 2-chloropyridine 112 was then subjected to a nickel(0)-mediated homo-coupling

reaction to afford the C2-symmetric chiral nonracemic 2,2'-bipyridyl ligand 113.

Scheme 1.9.4. Katsuki and Co-worker's Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligand

Reagents and condifions: (a) LDA, THF, -78 "C then acetone; (b) chiral HPLC resolution (Daicel

Chiracel OF column); (c) TBSOTf, 2,6-lutidine; (d) NiC12(H20)6, Zn dust, PPh3, DMF.

In an effort to achieve a more efficient synthesis of the ligand 113 that would

facilitate the preparation of this compound on a larger scale, Katsuki and co-workers have

- - - -

(62) Ito, K.; Katsuki, T. Synthesis of New Chiral Bipyridine Ligands and Their Application to Asymmetric

Cyclopropanation. Chem. Lett. 1994, 1857.

reported an asymmetric synthesis that did not rely on tedious resolution procedures

(Scheme 1.9.5.) .~~ The synthetic route began with the 2-chloropyridine 106a which was

deprotonated with lithium N,N-diisopropylamide and the resultant anion was reacted with

diphenyldiselenide. The product of this reaction was then oxidized with hydrogen

peroxide to the corresponding selenoxide that underwent elimination of phenylselenic

acid and afforded the 2-chloropyrindine 114. A subsequent manganese(II1)-catalyzed

asymmetric epoxidation reaction afforded the epoxide 115 in high enantiomeric excess

(96%).64 Treatment of this epoxide with 1-methylvinylcuprate provided the alcohol 116

as a single regioisomeric product. The alcohol 116 was then reacted with phenyl

chlorothioformate in the presence of N,N-dimethyl-4-aminopyridine to afford the

corresponding thiocarbonate. This compound was then reduced upon treatment with tri-

n-butyltin hydride and triethylborane to afford the alkene 117. The alkene 117 was then

reacted with m-chloroperoxybenzoic acid and the resultant epoxide was in turn reacted

with lithium triethylborohydride to afford the ring-opened tertiary alcohol 111. This

compound was then converted to the silylether 112 upon treatment with tert-

butyldimethylsilyl triflate. A subsequent nickel(0)-mediated homo-coupling reaction

afforded the C2-symmetric chiral nonracemic 2,2'-bipyridyl ligand 113 in high

enantiomeric excess (99.9%).

(63) Ito, K.; Yoshitake, M.; Katsuki, T. Chiral Bipyridine and Biquinoline Ligands: Their Asymmetric

Synthesis and Application to the Synthesis of trans-Whisky Lactone. Tetrahedron 1996, 52,3905.

(64) Fukuda, T.; Irie, R.; Katsuki, T. Mn-Salen Catalyzed Asymmetric Epoxidation of Conjugated

Trisubstituted Olefins. Synlett 1995, 197.

Scheme 1.9.5. Katsuki and Co-worker's Asymmetric Synthesis of the Chiral Nonracemic C2-

Symmetric 2,2'-Bipyridyl Ligand 113 using a Manganese(ll1)-Catalyzed Asymmetric Epoxidation

Reaction(l996)

106a 114 11 5 (96% ee)

f l ~ e TBSO Me

Reagents and conditions: (a) LDA, THF, -78 "C to -20 "C, 1 h then PhSeSePh, 10 min; (b) 31%

H202, NaHC03, EtOAcrrHF (2:1), 0 "C, 30 min, 72% (over two steps); (c) chiral Mn-salen

complex, NaCIO, 4-phenylpyridine-N-oxide, CH2CI2, 0 "C, 3 h, 89%; (d) t-BuLi, 2-bromopropene,

CuCN, THF, -78 "C, 10 min, 90%; (e) PhOC(S)CI, DMAP, MeCN, room temperature, 3 h;

purification by chromatography then n-Bu3SnH, BEt3, PhH, room temperature, 12 h, 40% (over

two steps); (f) m-CPBA, CH2CI2, 0 "C, 2.5 h, 76%; (g) LiBEt3H, THF, 0 "C, 1 h, 79%; (h) TBSOTf,

2,6-lutidine, CH2CI2, room temperature, 2 h, 91%; (i) NiC12(H20)6, Zn dust, PPh3, DMF, 50 OC, 12

h, 91%.

In 2000, Malkov and co-workers reported the synthesis of the chiral nonracemic

C2-symmetric 2,2'-bipyridyl ligand 123 using building blocks from the chiral pool

(Scheme 1 . ~ ) . 6 . ) . ~ ~ (+)-Nopinone 119, which was prepared from (-)-p-pinene 11 8 by

ozonolysis, was converted to the oxime 120. The oxime 120 was then reduced with zinc

dust in the presence of acetic anhydride to afford the enamide 121. Subsequent reaction

of this compound with N,N-dimethylforrnamide and phosphoryl chloride (Vilsmeier-

Haack conditions) afforded the 2-chloropyridine 122. A nickel(0)-mediated homo-

coupling reaction then provided the desired 2,2'-bipyridyl ligand 123.

Scheme 1.9.6. Malkov and Co-worker's Pinene-Derived Chiral C2-Symmetric 2,2'-Bipyridyl

Ligand 123 (PINDY) (2000)

Me d pNt0 -- pa2 (pq$

Me Me Me Me Me Me Me Me

121 122 123 (PINDY)

Reagents and conditions: (a) 0s04, Nal04, Me3N0, t-BuOH, 80 "C, 2 h, 64%; (b) NH20H.HCI,

pyridine, EtOH; (c) Fe powder, Ac20, AcOH, toluene, 0 "C, 10 min, 90%; (d) DMF, POC13, 0 "C, 1

h; (e) NiC12(H20)6, Zn dust, PPh3, DMF, 60 "C, 18 h, 32 %.

In 2001, Chelucci and co-workers reported an alternative synthesis of the 2,2'-

bipyridine ligand 123 that negated the need for the metal-mediated homo-coupling

(65) Malkov, A. V.; Bella, M.; Langer, V.; KoEovsky, P. PINDY: A Novel, Pinene-Derived Bipyridine and

its Application in Asymmetric, Copper(1)-Catalyzed Allylic Oxidation. Org. Lett. 2000,2, 3047.

reaction (Scheme 1 .9.7.).66 The difficulties often encountered in obtaining 2-

halopyridines such as the requirement for relatively harsh reaction conditions and low

reaction yields makes this report an important synthetic contribution. The synthetic

strategy involved sequential construction of the two pyridine rings. The synthetic route

began from racemic 3-benzyloxy-2-butanone 124. The pyridine 126 was obtained upon

addition of the lithium enolate of the benzylketone 124 to (lR,5R)-3-methylenenopinone

125, which was prepared from (-)-/?-pinene 118, followed by aza-anulation of the

resultant 1,5-dicarbonyl compound with ammonium acetate. The benzyl group was then

removed by a catalytic hydrogenolysis reaction to afford the alcohol 127 which was

subsequently oxidized under Swern conditions to afford the ketone 128. The second

pyridine ring was then constructed in an analogous fashion to afford the C2-symmetric

2,2'-bipyridine ligand 123 in 35% overall yield.

(66) Chelucci, G.; Saba, A. N e w Synthetic Route to C2-Symmetric 2,2'-Bipyridines: Synthesis of

(6R,6'R,8R,8R')-6,8,6',8'-Bismethano-7,7,7',7'-tetramethyl-5,5',6,6',7,7'-octahydro-2,2'-biquinoline.

Synth. Commun. 2001,31 ,3 161.

Scheme 1.9.7. Chelucci and Co-worker's Route to the Pinene-Derived Chiral C2-Symmetric

2,2'-Bipyridyl Ligand 123 (2001)

Reagents and conditions: (a) LDA, THF, -40 "C, 2 h then NH40Ac, AcOH, reflux, 3 h, 23%; (b)

Hz (3 atm), PdIC, EtOH, room temperature, 92%; (c) DMSO, (COC1)2, NEt3, -60 "C to room

temperature, 93%; (d) LDA, THF, -40 "C, 2 h then 3-methylenenopinone 125 then NH40Ac,

AcOH, reflux, 35%.

1.9.2. 2,2'-Bipyridines with Axial Chirality

Molecules in which the chirality is due to restricted rotation about a single bond

are said to contain axial chirality (atropisomeric). This type of chirality has been

incorporated successfully into ligands based on the 1,l '-binapthalene framework such as

B I N O L ~ ~ and B I N A P . ~ ~

(67) (a) Noyori, R. Centenary Lecture. Chemical Multiplication of Chirality: Science and Applications.

Chem. Soc. Rev. 1989, 18, 187. (b) Pu, L. 1,l'-Binapthyl Dimers, Oligomers, and Polymers: Molecular

Recognition, Asymmetric Catalysis and New Materials. Chem. Rev. 1998,98,2405.

(68) Noyori, R. BINAP: An Efficient Chiral Element for Asymmetric Catalysis. Acc. Chem. Rex 1990, 23,

345.

The first synthesis of an axially chiral 2,2'-bipyridyl ligand 136 was reported by

Wong and co-workers in 1990 (Scheme 1 .9.8.).69 The chirality of this novel ligand 136 is

due to the rigidity of the cyclooctatetraene core that has a high barrier to interconversion

of ring conformation. The synthesis of the ligand 136 began with the preparation of the

cyclooctenopyridine 131 by the condensation reaction of p-aminoacrolein 129 with

cyclooctanone 130 in the presence of ammonium acetate and triethylamine. The

cyclooctenopyridine 131 was then converted to the benzylidene 132 upon condensation

with benzaldehyde. The benzylidene 132 was then converted to the ketone 133 by

ozonolysis. The second pyridine ring was then constructed by thermolysis of the

corresponding 0-allyloxime 134, that was prepared by condensation of the ketone 133

with 0-allylhydroxylamine. Double benzylic bromination of the resultant 2,2'-bipyridine

135 with N-bromosuccinimide in carbon tetrachloride afforded a diastereoisomeric

mixture of dibromides. These compounds were then dehydrobrominated with alcoholic

potassium hydroxide to afford the racemic axially chiral 2,2'-bipyridyl ligand 136.

Resolution of this compound was accomplished by treatment of the racemic ligand 136

with a chiral palladium complex followed by fractional crystallization to afford a single

diastereoisomeric complex.

(69) Wang, X. C.; Cui, Y. X.; Mak, T. C. W.; Wong, H. N. C. Synthesis, Metal Complex Formation, and

Resolution of a New C2 Diazabiaryl Ligand: Cyclo-octa[2,1-b:3,4-b'ldipyridine. J. Chem. Soc., Chem.

Commun. 1990, 167.

Scheme 1.9.8. Wong and Co-worker's Novel Axially Chiral2,2'-Bipyridyl Ligand 136 (1 990)

Reagents and conditions: (a) NH40Ac, NEt3, 120 "C, 25%; (b) PhCHO, AczO, reflux, 8 days,

83%; (c) 03, CH2CI2, -40 "C then Me2S, 40%; (d) 0-allylhydroxylamine.HCI, NaOAc, Na2C03,

EtOH, reflux, 87%; (e) 180 "C, sealed tube, 52 h, 60%; (f) NBS, CCI4, reflux; (g) KOH, EtOH,

reflux, 70% (over two steps); (h) resolution by coordination to a chiral palladium complex.

In 1993, Botteghi and co-workers reported the synthesis of the axially chiral 2,2'-

bipyridyl ligand 140 in which the chirality is due to the restricted rotation about the biaryl

bond created by a chiral tartaric acid-derived macrocycle (Scheme 1 .9.9.).70 The

synthesis of this ligand began with a double nucleophilic displacement reaction of the

readily available ditosylate 138 with 2-bromo-3-hydroxypyridine that afforded the

bispyridine 139. A nickel(0)-mediated homo-coupling reaction then provided the axially

chiral2,2'-bipyridine ligand 140 as a single atropisomer.

(70) Botteghi, C.; Schionato, A.; De Lucchi, 0. A C2-symmetric Chiral 2,2'-Bipyridine Derived from

Tartaric Acid. Synth. Commun. 1991,21, 18 19.

Scheme 1.9.9. Botteghi and Co-worker's Tartrate Derived Axially Chiral 2,2'-Bipyridyl Ligand

Reagents and conditions: (a) 2,2-dimethoxypropane, p-TsOH (cat.) reflux; (b) LiAIH4, Et20,

reflux; (c) TsCI, 2,6-lutidine, CH2CI2; (d) 2-bromo-3-hydroxypyridine, NaOH, H20, n-Bu4NBr, 85

"C, 48 h, 95%; (e) NiC12(H20)6, Zn dust, PPh,, DMF, 50 "C, 20 h, 38%.

Chan and co-workers have described the synthesis of the axially chiral 2,2'-

bipyridyl ligands 144 and 145 (Scheme 1.9. In this case, the substituted pyridine

141 was brominated in the ortho-position on deprotonation with tert-butyllithium and

subsequent treatment with 1,2-dibromoethane. Demethylation of the resultant 2-

bromopyridylanisole 142 with 48% hydrogen bromide in acetic acid afforded the axially

chiral racemic phenol 143 which was then separated into its atropoisomers by preparative

chiral HPLC. A subsequent nickel(0)-mediated homo-coupling reaction of the chiral

nonracemic phenol 143 afforded the 2,2'-bipyridyl ligand 144 as a single stereoisomer.

Finally, methylation of the 2,2'-bipyridine 144 with dimethyl sulfate afforded the 2,2'-

bipyridyl ligand 145.

(71) Wong, H. L.; Tian, Y.; Chan, K. S. Electronically Controlled Asymmetric Cyclopropanation Catalyzed

by a New Type of Chiral2,2'-Bipyridine. Tetrahedron Lett. 2000, 41, 7723.

Scheme 1.9.10 Chan and Co-worker's Axially Chiral 2,2'-Bipyridyl Ligands 144 and 145 (2000)

t-Bu OMe t-BU - OMe t-BU - OH

/

Reagents and conditions: (a) t-BuLi (1.5 equiv), THF, -78 "C, 1 h then 1,2-dibromoethane, -78 "C

to room temperature, 4 h, 71%; (b) 48% HBrIAcOH, 120 "C, 8 h, 95%; (c) HPLC resolution

(Daicel Chiracel OD column); (d) Ni(PPh3)2C12 (1 equiv), Zn dust (2 equiv), Et4NI (1.5 equiv), THF,

60 "C, 8 h, 89%; (e) NaOH (2 equiv), MeOH, room temperature, 1 h then Me2S04 (2 equiv), 40

"C, 2 h, 90%.

1.9.3. 2,2 '-Bipyridines with Planar Chirality

Molecules with chirality that originates from the arrangement of out-of-the-plane

substituents relative to a reference plane are said to have "planar chirality". There are

several examples of 2,2'-bipyridyl ligands that contain elements of planar chirality. In

1999, Vogtle and co-workers reported the synthesis of the planar chiral 2,2'-bipyridyl

ligand 153 (Scheme 1.9.1 1 .).72 The synthesis began from 2,5-pyridinedicarboxylic acid

145 which was converted to the diethyl ester 147 via the diacid chloride. The diester 147

(72) Worsdorfer, E.; Vogtle, F.; Nieger, M.; Waletzke, M.; Grimme, S.; Glorius, F.; Pfaltz, A. A New

Planar Chiral Bipyridine Ligand. Synthesis 1999, 597.

was then reduced with sodium borohydride in the presence of calcium chloride to afford

the diol 148 which was then converted to the dibromide 149 upon treatment with 30%

hydrogen bromide in acetic acid. The dibromide 149 was then coupled with 1,4-

bis(sulfanylmethyl)benzene, under high dilution and taking advantage of the cesium

template effect, to afford the bis(thioether) 150. Irradiation of the bis(thioether) 150 with

UV light (Hg, 180 W) in the presence of trimethoxyphosphine provided the cyclophane

151. This material was then oxidized with m-chloroperoxybenzoic acid to the

corresponding N-oxide which was then converted to the nitrile 152 upon reaction with

trimethylsilyl cyanide and dimethylcarbamyl chloride. The final step in the synthesis was

a cobalt(1)-catalyzed cyclotrimerization of the nitrile 152 with acetylene that afforded the

racemic 2,2'-bipyridyl ligand 153. The racemic compound 153 was resolved by

preparative chiral HPLC. The absolute stereochemistry was then assigned by comparison

of the experimental and theoretical CD spectra.

Scheme 1.9.1 1. Vogtle and Co-worker's Planar Chiral2,2'-Bipyridyl Ligand 153 (1999)

Reagents and conditions: (a) SOCI2, reflux, 8 h, then EtOH, reflux, 2 h, 82%; (b) NaBH4 (2

equiv), CaCI2 (1 equiv), EtOH, room temperature, 16 h, 67%; (c) 30% HBrIAcOH, room

temperature, 6 days; (d) 1,4-bis(sulfanylmethyI)benzene (1 equiv), KOt-Bu (2.3 equiv), Cs2C03,

EtOH, reflux, 16 h, 62%; (e) P(OMe)3, hv (Hg, 180W), room temperature, 18 h, 84%; (f) m-CPBA

(2 equiv), CH2CI2, room temperature, 20 h then N,N-dimethylcarbamoyl chloride (1.3 equiv),

TMSCN (1.3 equiv), CH2CI2, room temperature, 16 h, 75%; (g) cyclopenatdienylcycloocta-l,5-

dienecobalt (2 equiv), C2H2 (1.5 bar), PhCH3, 120 "C, 20 h, 23% then resolution by chiral HPLC.

In 2000, the synthesis of a novel C2-symmetric 2,2'-bipyridyl ligand 159 with

planar chirality was reported by Fu and co-workers (Scheme 1.9.12.)~~ The synthesis of

the ligand 159 began from the known pyridine-2-01 154 which was converted to the

chloride 155 upon reaction with phosphoryl chloride. The chloride 155 was then

oxidized to the corresponding N-oxide which upon heating with acetic anhydride

afforded the acetate 156. Elimination of the acetate with sulfuric acid afforded the

(73) Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C. Synthesis, Resolution and Crystallographic

Characterization of a New C2-Symmetric Planar-Chiral Bipyridine Ligand: Application to the Catalytic

Enantioselective Cyclopropanation of Olefins. Chem. Commun. 2000, 377.

pyrindine 157 as a mixture of regioisomers. The pyrindine 157 was then complexed with

iron(I1) via reaction of its lithium salt, obtained by deprotonation with n-butyllithium,

with Cp"FeC1 to afford the ferrocene derivative 158. This compound then underwent a

nickel(0)-mediated homo-coupling reaction to afford the desired Cz-symmetric planar

chiral2,2'-bipyridine ligand 159 as a single diastereoisomer in racemic form. Resolution

was accomplished by preparative chiral HPLC and the absolute stereochemistry was

established by X-ray crystallography.

Scheme 1.9.12 Fu and Co-worker's Novel Planar Chiral2,Z'-Bipyridyl Ligand 159 (2000)

Me

Reagents and Conditions: (a) POCI3, 74 %; (b) H202, AcOH, 88%; (c) Ac20, 58%; (d) H2S04,

79%; (e) n-BuLi then Cp'FeCI, 58%; (f) Ni(PPh3)Brz, Zn dust, EtNI, 58% then resolution by chiral

HPLC (Regis Whelk-0 column).

1.9.4. Catalytic Asymmetric Cyclopropanation Reactions

The copper(1)-catalyzed asymmetric cyclopropanation reaction (AC) of alkenes

160 with diazoesters 161 to afford the diastereoisomeric trans- and cis-cyclopropanes

162 has become the standard "benchmark" reaction by which new chiral 2,2'-bipyridyl

ligands are evaluated (Scheme 1.9.13.).~~ The two main driving forces for the use of the

copper(1)-catalyzed AC reaction are the excellent results that have been obtained in this

reaction with the structurally related chiral bisoxazoline ligands as well as the high

affinity of 2'2'-bipyridine ligands for copper salts.

Scheme 1.9.13. Copper(1)-Catalyzed Asymmetric Cyclopropanation Reactions of Alkenes

161

CuOTf, L*, CH2C12 1;02R1 ~ 0 2 ~ ' I *

slow addition of diazoester 4 + R2 R2

The catalytic AC reaction of alkenes is a reaction which is used extensively in

synthesis.75 For instance, Aratani who was a student of Nozaki (one of the pioneers of

catalytic asymmetric synthesis) developed a highly enantioselective synthesis of 2,2'-

dimethyl-cyclopropane-1-carboxylic acid ethyl ester 165 at the Sumitomo Chemical

Company that was incorporated into the commercial production process of Merck's

antiobiotic drug, cilastatin 166 (Scheme 1.9.14.).~~

(74) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Gtalytic Methods for Organic Synthesis with Diazo

Compounds; J . Wiley: New York, 1998.

(75) For recent reviews on AC reactions, see: (a) Doyle, M. P.; Forbes, D. C. Recent Advances in

Asymmetric Catalytic Metal Carbene Transformations. Chem. Rev. 1998, 98, 91 1. (b) Doyle, M. P.;

Protopopova, M. N. New Aspects of Catalytic Asymmetric Cyclopropanation. Tetrahedron 1998, 54,79 19.

(76) (a) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Asymmetric Synthesis of Chrysanthemic Acid. An

Application of Copper Carbenoid Reaction. Tetrahedron Lett. 1975, 1707. (b) Aratani, T.; Yoneyoshi, Y.;

Nagase, T. Asymmetric Synthesis of Permethric Acid. Stereochemistry of Chiral Copper Carbenoid

Reaction. Tetrahedron Lett. 1982, 23, 685. (c) Aratani, T. Catalytic Asyrnmetric-Synthesis of

Cyclopropane-Carboxylic Acids - An Application of Chiral Copper Carbenoid Reaction. Pure Appl. Chem.

1985,57, 1839.

Scheme 1.9.14. Industrial Synthesis of Cilastatin 166 using a Catalytic Asymmetric

Cyclopropanation Reaction

163 165 (92% ee) 166 (cilastatin)

Reagents and conditions: (a) 1.0 mol % copper-complex 167, CH2CI2, room temperature.

The generally accepted mechanism for the copper(1)-catalyzed AC reaction of

alkenes with diazo compounds involves three fundamental steps (Figure 1.9.1 .). The first

step is the nucleophilic addition of the diazo compound to an electrophilic copper(1)-

catalyst that affords the diazonium ion 168. The second step is the elimination of

dinitrogen to form a copper stabilized carbene 169 which, in the third step, is transferred

to an alkene 160 (electron-rich substrate) to form a cyclopropane 170 and regenerate the

copper(1)-catalyst 171.

Increasing Stability

Increasing Reactivity

Figure 1.9.2. The relationship between diazo compound structure and reactivity (R = alkyl).

Transition metal carbene intermediates react readily with electron rich substrates

such as alkenes. These intermediates may be depicted by three resonance structures: a

formal metal carbene 176; an ylide or metal stabilized carbocation 177; and a metal

stabilized carbene 178, that illustrate the electrophilic nature of these transition metal

carbenes (Figure 1.9.3 .).

Figure 1.9.3. The contributing resonance structures of a metal carbene complex.

Three methods have been employed to carry out copper(1)-catalyzed

cyclopropanation reactions. The first and most direct method involves the use of

copper(1) trifluoromethanesulfonate as the copper(1) source. However, this method

requires considerable experimental care to ensure the integrity of this highly air and

moisture sensitive reagent (Method A ) . ~ ~ The second method uses the more stable

copper(I1) trifluoromethanesulfonate as the copper source, that is reduced to the

(79) Salomon, R. G.; Kochi, J. K. Copper(1) Catalysis in Cyclopropanations with Diazo Compounds. The

Role of Olefin Coordination. J. Am. Chem. Soc. 1973, 95, 3300.

corresponding catalytically active copper(1) species with either phenylhydrazine or a

slight excess of the diazoester (Method B).~',~' In the third method, a copper(I1) chloride

ligand complex is synthesized and then converted into the corresponding

bis(trifluoromethanesu1fonate) on treatment with silver trifluoromethanesulfonate. The

catalytically active copper(1) species is then obtained by reduction with either

phenylhydrazine or a slight excess of the diazoester (Method c ) . ~ ~ In all instances, the

diazoester is added slowly over the course of several hours to the reaction mixture, which

contains an excess of the alkene, to avoid the undesired coupling reaction of two

molecules of the diazoester to afford the corresponding fimarates.

For CI-symmetric 2,2'-bipyridine ligands, the enantioselectivities and

diastereoselectivities that have been achieved in copper(1)-catalyzed asymmetric

cyclopropanation reactions of styrene with diazocompounds have been low. For

instance, the planar chiral cyclophane-derived 2,2'-bipyridine ligand 153 that was

reported by Vogtle and co-workers effected reactions with low enantioselectivities (5

26% ee).72

C2-symmetric 2,2'-bipyridyl ligands have been found to perform well in

cyclopropanation reactions. Bolm and co-worker's ligand 99 afforded the trans-

cyclopropane in high enantiomeric excess (up to 92%).58 In the case of the series of

(80) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Semicorrin Metal Complexes as Enantioselective Catalysts.

Part 2. Enantioselective Cyclopropane Formation fiom Olefins with Diazo Compounds Catalyzed by

Chiral (Semicorrinato)copper Complexes. Helv. Chim. Acta. 1988, 71, 1553.

(81) Lowenthal, R. E.; Abiko, A.; Masamune, S. Asymmetric Catalytic Cyclopropanation of Olefins:

bis(Oxazo1ine) Copper Complexes. Tetrahedron Lett. 1990, 31, 6005.

(82) Kwong, H.-L.; Lee, W.-S.; Ng, H.-F.; Chiu, W.-H.; Wong, W.-T. Chiral Bipyridine-Copper(I1)

Complex. Crystal Structure and Catalytic Activity in Asymmetric Cyclopropanation. J. Chem. Soc., Dalton

Trans. 1998, 1043.

ligands llOa,b and 113 reported by Katsuki and co-workers, high enantioselectivities

were also achieved. 6 1,62,63 Employment of the a,af-dimethyl substituted ligand llOa

afforded the trans-cyclopropane in good enantioselectivity (77% ee) while employment

of the bulkier ligand 113 afforded the trans-cyclopropane with improved

enantioselectvity (83% ee). The C2-symmetric axially chiral 2,2'-bipyridine ligand 145

reported by Chan and co-workers was applied to the cyclopropanation reaction of styrene

with ethyl d ia~oaceta te .~~ At room temperature, the trans-cyclopropane was obtained in

good enantiomeric excess (79%), which was improved (86% ee) upon decreasing the

reaction temperature to 0 OC. A strong electronic effect was also noted with the ligand

145 in which p-substituted styrenes with electron withdrawing groups underwent

cyclopropanation reactions in higher enantioselectivities than those with electron

donating groups. Fu and co-worker's C2-symmetric planar chiral 2,2'-bipyridine ligand

159 was also evaluated in the cyclopropanation reaction of styrene and 2,6-di-t-butyl-4-

methylphenyl diazoacetate which afforded the trans-cyclopropane product in high

diastereoisomeric and enantiomeric excess (94% de, 87% ee)." Of note, the high

diastereoselectivity in this particular reaction can be attributed to the large size of the 2,6-

di-t-butyl-4-methylphenyl substituent of the diazo compound.

1.9.5. Catalytic Asymmetric Allylic Oxidation Reactions

In 1959, Kharasch and Sosnovsky reported the allylic oxidation reaction of

alkenes, such as cyclohexene, using a catalytic amount of copper(1) bromide and tert-

butyl peroxybenzoate 179 as the stoichiometric oxidant in benzene at reflux. This

afforded the allylic ester product 180 in good yield (70%) (Scheme 1.9.15.).'~

Scheme 1.9.15. The Copper(1)-Catalyzed Allylic Oxidation Reaction

CuBr (cat.), benzene, 0

K reflux, 24 h 0 + p h A o - o t - ~ u w

70%

(excess) 179 180

The generally accepted mechanism for this copper(1)-catalyzed allylic oxidation

reaction involves four steps (Figure 1.9.4.). The first step is a copper-mediated homolytic

cleavage of the oxygen-oxygen bond in the tert-butyl peroxybenzoate 179 that generates

the copper(I1) carboxylate 181 and the tert-butoxy radical 182. The next step is the

abstraction of the hydrogen atom from the alkene substrate 183 by the tert-butoxy radical

that affords the thermodynamically more stable allylic radical 184 and tert-butanol.

While no detailed lunetic measurements have been made, these first two steps are thought

to be rapid and essentially diffusion ~ontrolled.'~ he third step is the addition of the

allylic radical 184 to the copper(I1) carboxylate 181 that affords the copper(II1) species

185. The final step of the reaction involves a pericyclic rearrangement or a reductive

elimination process that affords the reaction product 186 and regenerates the active

copper(1) catalyst 187.

(83) Kharasch, M. S.; Sosnovsky, G.; Yang, N. C. Reactions of tert-Butyl Peresters I. The Reaction of

Peresters With Olefins. J. Am. Chem. Soc. 1959, 81, 5819.

(84) Andrus, M. B.; Chen, X. Catalytic Enantioselective Allylic Oxidation of Olefins with Copper(1)

Catalysts and New Perester Oxidants. Tetrahedron 1997, 53, 16229.

Figure 1.9.4. Mechanism for the copper(1)-catalyzed asymmetric allylic oxidation reaction of

alkenes.

Asymmetric versions of this allylic oxidation reaction using chiral bisoxazoline

copper@)-complexes were reported independently in 1995 by Pfaltz and co-workers and

Andrus and co-workers (Scheme 1.9.16.).~' ,~~ Enantioselectivities of up to 80% ee for

the oxidation reaction of cyclic alkenes were achieved when the reactions were

performed in acetonitrile at relatively low temperatures (-20 "C).

(85) Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A. Enantioselective Allylic Oxidation Catalyzed by Chiral

bis(Oxazo1ine)-Copper Complexes. Tetrahedron Lett. 1995,36, 183 1 .

(86) Andrus, M. B.; Argade, A. B.; Chen, X.; Pamrnent, M. G. The Asymmetric Kharasch Reaction.

Catalytic Enantioselective Allylic Acyloxylation of Olefins with Chiral Copper(1) Complexes and tert-

Butyl Perbenzoate. Tetrahedron Lett. 1995, 36, 2945.

Scheme 1.9.16. Asymmetric Allylic Oxidation Reaction Catalyzed by the Chiral Copper(1) Triflate

bis(0xazoline) Complex 54

One of the most attractive features of this asymmetric copper(1)-catalyzed allylic

oxidation reaction is the usefulness of the reaction products in target-oriented synthesis.

A notable example, reported by Wallace and co-workers, is the use of (5')-cyclohexenyl

benzoate 188 to synthesize the chiral aldehyde 189 which is a key intermediate in the

synthesis of the inflammation mediator leukotriene B4 190 (Scheme 1.9.1 7.).87 The two-

step asymmetric preparation of the chiral aldehyde 189 by catalytic means represents a

marked improvement over previous routes which required multiple steps from

carbohydrate based starting materials.

Scheme 1.9.17. Synthesis of Leukotriene B4 190

5 mol % L* 54, 5 mol % Cu(OTf), OBz

MeCN, -20 OC >

0

(excess) p h K o , ~ t - ~ u 179 188 (80% ee)

OBz

t-Bu 54 3-Bu

03, MeOH, NaHC03,

Ac20, pyridine w

OBz 0

leukotriene Ba 190

High enantioselectivities have subsequently been achieved in this reaction (up to

99% ee). However, there remains a significant problem in that the catalytic systems

suffer from very sluggish reaction rates.84 in some cases, the reaction has taken up to one

(87) Hayes, R.; Wallace, T. W. A Simple Route to Methyl (5S)-Benzoyloxy-6-oxohexanoate, a Key

Intermediate in Leukotriene Synthesis. Tetrahedron Lett. 1990, 31, 3355.

month to reach a satisfactory level of c o n v e r s i ~ n . ~ ~ It has been found that chiral C2-

symmetric 2,2'-bipyridine copper(1)-complexes are very active catalytic systems for this

reaction in that they provide much faster reaction rates although the enantioselectivities

obtained thus far have been somewhat lower than with bisoxazoline complexes.

Malkov and co-worker's chiral C2-symmetric 2,2'-bipyridine ligand (PINDY) 123

formed an extremely active catalytic system which was able to oxidize cyclohexene with

1 mol % catalyst loading in less than 30 min at room temperature, to afford the benzoate

product 188 in high yield (96%) and in moderate enantioselectivity (49% ee).65 The

enantioselectivity was improved (55% ee) when the reaction was conducted at 0 OC, but

the reaction required 5 h in this instance. Similar results were obtained in the asymmetric

oxidation of cyclopentene (48% ee at room temperature and 59% ee at 0 O). When

cycloheptene was used as the substrate, substantially increased enantioselectivities were

observed (62% ee at room temperature and 75% ee at 0 OC). Thus, with optimization of

the ligand structure, a catalyst system based on a 2,2'-bipyridine framework may be

capable of providing excellent enantioselectivities and reaction rates in this

enantioselective allylic oxidation reaction.

1.10. Chiral2,2'-Bipyridine Mono- and Bis-N-Oxides

Recently, several examples of the mono- and his-N-oxides of chiral 2,2'-

bipyridine ligands have been reported. Malkov and co-workers have reported the

preparation of both the corresponding mono- and his-N-oxides of their chiral 2,2'-

(88) Andrus, M. B.; Zhou, Z. Highly Enantioselective Copper-bisoxazoline-Catalyzed Allylic Oxidation of

Cyclic Olefins with tevt-Butyl p-Nitroperbenzoate. J. Am. Chem. Soc. 2002, 124, 8806.

bipyridine ligand PINDY 123 (Scheme 1.10.1.).~~ Oxidation of PINDY 123 with m-

chloroperoxybenzoic acid at lower temperature (0 "C, 45 min) led exclusively to the

mono-N-oxide 192 while oxidation at room temperature led to the bis-N-oxide 194. In

this paper the preparation of 3,3'-dimethyl-PINDY 191 and its oxidation to the bis-N-

oxide 193 was also reported. Of note, this ligand now contains both stereogenic centres

and an element of axial chirality. The two diastereoisomers of these atropisomers were

separated by chromatography on silica gel.

Scheme 1.10.1. Synthesis of Mono- and Bis-N-Oxides of the Chiral Nonracemic C2-Symmetric

2,2'-Bipyridyl Ligand 123 (2002)

(+)-I23 (R = H) (+)-I91 (R = Me)

R R

a

Me & Me - Me Me

(+)-I 92 (R = H) (+)-I92 (R = Me) (-)-I93 (R = Me)

Reagents and conditions: (a) m-CPBA, CH2CI2, 0 "C, 30 min, 96% [(+)-1921; (b) m-CPBA,

CH2CI2, room temperature, 24 h, 62% [(-)-1941.

(89) Malkov, A. V.; Orsini, M.; Pemazza, D.; Muir, K. W.; Langer, V.; Meghani, P.; KoEovsky, P. Chiral

2,2'-Bipyridine-Type N-Monoxides as Organocatalysts in the Enantioselective Allylation of Aldehydes

with Allyltrichlorosilane. Org. Lett. 2002, 4, 1047.

In 2002, Hayashi and co-workers reported the synthesis of the novel axially chiral

2,2'-bipyridyl his-N-oxide 199 (Scheme l . l 0 . 2 . ) . ~~ For the preparation of compound

199, a new method of introducing and fixing the axial chirality by oxidation of the cyclic

diester 197 was developed. The bipyridine-diol 196 was prepared by oxidation of 2,9-

diphenylphenanthroline 195 with potassium permanganate and sodium periodate

followed by esterification of the resultant dicarboxylic acid and subsequent reduction

with lithium aluminum hydride. The diol 196 was then coupled with (R)-2,2'-

bis(chlorocarbony1)- 1,l '-binapthalene in the presence of triethylamine to afford the cyclic

diester 197 in high yield. On heating the cyclic diester 197 in toluene, the

thermodynamically more stable diastereoisomer 197 was obtained as a single

stereoisomer. The absolute configuration of this 2,2'-bipyridine was assigned as (R) by

X-ray crystallography. Oxidation of the 2,2'-bipyridine 197 with m-chloroperoxybenzoic

acid followed by alkaline hydrolysis of the esters gave the enantiomerically pure bis-N-

oxide (R)-199. Here, the axial chirality was now fixed by the restricted rotation about the

2,2'-bipyridine axis that was imposed by the two N-oxide moieties.

(90) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. A Novel Axially Chiral 2,2'-Bipyridine N,N'-Dioxide.

Its Preparation and use for Asymmetric Allylation of Aldehydes with Allyl(trichloro)silane as a Highly

Efficient Catalyst. Org. Lett. 2002,4, 2799.

Scheme 1.10.2. Hayashi and Co-worker's Novel Synthesis of the Axially Chiral 2,2'-Bipyridyl

bis-N-Oxide 199 (2002)

Reagents and Conditions: (a) KMn04, Na104, K2CO3, t-BuOH, H20, reflux, 14 h, 39%; (b) CH2N2,

Et20, room temperature, < I0 min, 35%; (c) LiAIH4, THF, room temperature, 2 h, 88%; (d) (R)-

2,2'-bis(chlorocarbonyl)-1,l'-binapthalee, NEt3, CHCI3, room temperature, 24 h; (e) PhMe,

reflux, 48 h, 75% (over two-steps); (f) m-CPBA, CH&, room temperature, 64 h, 71%; (g) 6 M

NaOH, MeOH, room temperature, 31 h, 100%.

Denmark and co-workers have reported the synthesis of several chiral 2,2'-

bipyridyl bis-N-oxides related to the bipyridine ligand 99 and 200 that were first reported

by Bolrn and co-workers (Scheme 1. I O . ~ . ) . ~ ' The target his-N-oxides 201 and 202 were

obtained upon oxidation with m-chloroperoxybenzoic acid.

(91) Denmark, S. E.; Fan, Y. Catalytic, Enantioselective Aldol Additions to Ketones. J. Am. Chem. Soc.

2002,124,4233.

Scheme 1.10.3. Denmark and Co-worker's Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl

Ligand Bis-N-Oxide 201 and 202 (2002)

(R,R)-99 (R = Me) (R, R)-201 (R = Me) (R,R)-200 (R = n-Bu) (R, R)-202 (R = n-Bu)

Reagents and conditions: (a) m-CPBA, CH2CI2, room temperature, 12 h , 95% [(R,R)-2011, 96%

[(R, R)-2021.

In the same paper, Denmark also reported the synthesis of the related axially

chiral 3,3 '-dimethyl his-N-oxides 208 (Scheme 1.10.4.). The key step in the synthesis

was a novel anionic coupling reaction of the mono-N-oxide 207. Directed lithiation with

lithium tetramethylpiperamide at -78 "C at the 2-position of the pyridine was directed by

the N-oxide moiety. Subsequent addition of half an equivalent of iodine afforded the

axially chiral his-N-oxide 208 as a single atropisomer in 48% yield. To obtain the other

atropisomer, the N-oxide moieties of 208 were reduced with zinc in acetic acid to afford

the corresponding 3,3'-dimethyl-2,2'-bipyridine which was subsequently re-oxidized

with m-chloroperoxybenzoic acid to afford a mixture of diastereoisomers which were

separated by flash column chromatography.

Scheme 1.10.4. Denmark and Co-worker's Axially Chiral 2,2'-Bipyridyl bis-N-Oxides 208 (2002)

a b

- / \

---+ Me-::

(R)-205 (95% ee)

d 7 - --

-N On-Bu

(R)-206

e P

- On-Bu

0 - (R)-207 *

t-BU ,-

t-BU , - /I On-Bu

(P)-(R, R)-208 (M)-(R, R)-208

Reagents and conditions: (a) n-BuLi, Et20, -78 "C, 1 h then pivaloyl chloride (2.0 equiv), -78 "C

to room temperature, 90%; (b) (-)-(ip~)~BCl (1.5 equiv), neat, room temperature, 2 h, 84%; (c) n-

BuBr, KOH, THF, 18-crown-6, DMF, room temperature, 84%; (d) m-CPBA, CH2CI2, room

temperature, 12 h, 84%; (e) LiTMP, -73 "C, 16 h then l2 (0.5 equiv), -73 "C to room temperature,

48%; (f) Zn dust, AcOH, room temperature, 12 h, 91%; (g) m-CPBA. CH2CI2, room temperature,

12 h then chromatographic separation of the diastereoisomers afforded 27% [(M)-(R,R)-2081 and

67% [(P)-(R, R)-2081.

Chiral 2,2'-bipyridine mono- and bis-N-oxides have been used as organocatalysts

in asymmetric synthesis. In the following section, a brief discussion of these applications

is presented.

1.11. Asymmetric Allylation and Aldol Reactions with 2,2'-Bipyridine

Mono- and bis-N-Oxides

Chiral nonracemic 2,2'-bipyridine mono- and bis-N-oxides have been found to be

excellent asymmetric organocatalysts for the activation of silicon reagents towards

reaction with electrophiles (Scheme 1.1 1.1 .).90

Scheme 1 .I 1 . I . Catalytic Asymmetric Allylation Reactions of Aldehydes

L*, (i-PrhNEt, CH2CI2 or MeCN, low temperature I)H

Ar + R1*sic13 * ~r

R2 R' k2

Malkov and co-worker's chiral 2'2'-bipyridine bis-N-oxide 194 was found to

catalyze the addition of allyltrichlorosilane 210 (R' and R~ = H) to benzaldehyde 209 and

afforded the product (R)-211 in moderate enantiomeric excess (41%) when the reaction

was performed at -90 O C . ~ ~ A considerable improvement in enantioselectivity (92% ee)

was obtained when the Malkov and co-worker's chiral2,2'-bipyridine mono-N-oxide 192

was used as the catalyst at -90 OC. Further studies with this catalyst 192 revealed that the

enantioselectivity is highly dependant on the nature of the aldehyde substrate. In

particular, aromatic aldehydes were found to be much better substrates than aliphatic

aldehydes. Malkov and co-workers envisioned that the efficiency of the reaction could

be improved if the rotation about the 2,2'-bipyridine bond was restricted. As such, the

chiral 3,3'-dimethyl-2,2'-bipyridine mono-N-oxide 192 was prepared and as expected the

rotation barrier about the bipyridine bond was high and the atropisomers could be

isolated by chromatography. In the reaction of allyltrichlorosilane 210 with

benzaldehyde 209, the atropisomer (Rax)-(+)-I92 induced the formation of the product

(59-211 in excellent enantiomeric excess (98%) at -60 OC.* In contrast, the opposite

atropisomer (Sax)-(-)-I92 gave the product (R)-211 in lower enantiomeric excess (82%).

This demonstrated that the sense of asymmetric induction was controlled mainly by the

chiral axis in the ligand and then amplified by the matched chirality of the pinene moiety

in the former case.

Hayashi and co-worker's axially chiral phenyl substituted 2,2'-bipyridine bis-N-

oxide (R)-199 has been shown to have a remarkably high catalytic activity in the

allylation reaction of aromatic aldehydes.90 When 1 mol % of this catalyst was

employed, the allylation of p-methoxybenzaldehyde was complete in just 15 min and

afforded the corresponding product in high enantiomeric excess (94%). The catalyst

loading can be reduced to 0.01 mol % without significant loss in enantioselectivity.

However, in this case, the reaction time required was 12 h. It was suggested that 71-71

stacking interactions between the aromatic group on the aldehyde substrate and the

phenyl ring on the catalyst could account for the high catalytic activity because aliphatic

aldehydes proved to be much less reactive under identical conditions.

Chiral 2,2'-bipyridine bis-N-oxides have also been shown to perform well in the

asymmetric addition reaction of silyl en01 ethers 213 to ketones 212 (Scheme 1 . 1 1 .2.).91

Scheme 1 . I 1.2. Catalytic Asymmetric Addition Reactions of Silyl Enol Ethers to Ketones

0SiCl3 L*, CH2CI2, -20 "C OH 0

+ A O M e b RiaOMe R*

- -

(*) The abbreviations (R,) and (S,,) refer to the absolute stereochemistry of the 2,2'-bipyridine axis.

The chiral 2,2'-bipyridine bis-N-oxide 202 reported by Denmark and co-workers

was found to catalyze the addition of trichlorosilyl ketene acetal213 to acetophenone 212

and afforded the P-hydroxyester 214 in good enantiomeric excess (64%). Restriction of

the rotation about the 2,2'-bipyridine bond via the installation of methyl groups at the 3

and 3' positions to afford the atropisomeric 3,3'-dimethyl-2,2'-bipyridine bis-N-oxides

208 was found to improve the catalyst efficiency. This again indicated that the reaction is

controlled mainly by the axial chirality of the ligand. As such, the atropisomer (S,,)-208

with matched stereogenic centres and axial chirality afforded the product in good

enantiomeric excess (84%) while the mismatched catalyst (R,)-208 afforded the opposite

enantiomer of the product in much lower enantiomeric excess (43%).

1.12. Chiral Nonracemic Pyridylphosphine Ligands (Pa-Ligands)

To date, a diverse group of chiral P,N-ligands that contain nitrogen and

phosphorus donor atoms have been synthesized and evaluated in catalytic asymmetric

reactions.92 P,N-ligands are of considerable interest in catalysis because of the unique

reactivity of their metal complexes which results from the electronic differences between

the two donor atoms. The strong trans-effect is well established in ~ f l - l i g a n d s . ~ ~ The

following sections concern a brief review of the syntheses of several known chiral

nonracemic pyridylphosphine ligands and their applications in catalytic asymmetric

reactions.

(92) For a review on chiral pyridylphosphine ligands, see: Chelucci, G.; O h , G.; Pinna, G. A. Chiral P,N-

Ligands with Pyridine-Nitrogen and Phosphorus Donor Atoms. Syntheses and Applications in Asymmetric

Catalysis. Tetrahedron 2003,59, 9471.

(93) For a detailed discussion on the trans-effect in P,N-ligands, see: Helmchen, G.; Pfaltz, A.

Phosphinooxazolines - A New Class of Versatile, Modular P,N-Ligands for Asymmetric Catalysis. Acc.

Chem. Rex 2000,33,336.

1.12.1. Chiral Pyridylphosphine Ligands With Stereogenic Centres

In 1996, Chelucci and co-workers reported the synthesis of PYDIPHOS 222, a

chiral nonracemic P,N-ligand derived from L-(+)-tartaric acid (Scheme 1.12.1 .).94 The

synthesis began from the diol215 which was prepared according to a literature procedure

and was subsequently mono-protected with tert-butyldiphenylsilyl chloride to furnish the

alcohol 216. Following Swern oxidation, the aldehyde 217 was converted to the nitrile

219 via treatment of the corresponding oxime 218 with N,N'-carbonyldiimidazole. A

cobalt(1)-catalyzed cyclotrimerization reaction of the nitrile 219 with two equivalents of

acetylene afforded the pyridine 2 2 0 . ~ ~ The hydroxyl moiety was then deprotected using a

solution of tetra-n-butylammonium fluoride in tetrahydrofuran to afford the

corresponding alcohol which was subsequently converted to the tosylate 221.

Nucleophillic displacement of the tosylate with potassium diphenylphosphide afforded

the chiral nonracemic pyridylphosphine ligand 222.

(94) Chelucci, G.; Cabras, M. A.; Botteghi, C.; Basoli, C.; Marchetti, M. Synthesis of Homochiral Pyridyl,

Bipyridyl and Phosphino Derivatives of 2,2-Dimethyl-1,3-dioxolane: Use in Asymmetric Catalysis.

Tetrahedron: Asymmetry 1996, 7, 885

(95) Varela, J. A,; Saa, C. Construction of Pyridine Rings by Metal-Mediated [2+2+2] Cycloaddition.

Chem. Rev. 2003,103,3787.

Scheme 1.12.1. Chelucci and Co-worker's Chiral P,N-Ligand PYDIPHOS 222 derived from

Tartaric Acid (1 996)

Me Me Me Me x x Me Me

0 0 a 0 0 b - - x x A

0 0

HOH2C CH20H HOH2C CH20TPS OHC x CH20TPS

Me Me Me Me

c d e . x 0 0 . x

0 0

A P

H 4 C H 2 O T P S NC CH20TPS

NOH

21 8 219

Reagents and conditions: (a) NaH (1 equiv), TPSCI, 75%; (b) (COCI)2, DMSO; NEt3, -78 "C to

room temperature, 89%; (c) NH20H-HCI, 10% K2CO3; (d) N,N~carbonyldiimida~oIe, 89% (over

two steps); (e) CpCo(COD), acetylene (14 atm), toluene, 120 "C, 94%; (f) n-Bu4NF, THF, 83%;

(g) TsCI, NEt3, DMAP, CH2C12; (h) PPh3, NaIK, dioxane, 67%.

Katsuki and co-workers have reported the synthesis of the chiral nonracemic 2-

(phosphinoaryl)pyridine ligands 227a-f (n = 1 or 2 and R = Ph, i-Pr and CMe20TBS)

(Scheme 1.12.2.).~~ The syntheses began from the chiral2-chloropyridines 223a-f, which

had been previously used in the preparation of chiral2,2'-bipyridine ligands6' A Suzuki

coupling reaction with o-hydroxyphenylboronic acid afforded the pyridylphenols 224a-f

(96) Ito, K.; Kashiwagi, R.; Iwasaki, K.; Katsuki, T. Asymmetric Allylic Alkylation using a Palladium

Complex of Chiral2-(Phosphinoary1)pyridine Ligands. Synlett 1999, 10, 1563.

which were then converted to the triflates 225a-f upon reaction with triflic anhydride in

the presence of 2,6-lutidine. A palladium-catalyzed coupling reaction of the triflates

225a-f with diphenylphosphine oxide furnished the phosphine oxides 226a-f which were

converted to the desired chiral 2-(phosphinoary1)pyridine ligands 227a-f on reduction

with trichlorosilane and triethylamine.

Scheme 1.12.2. Katsuki and Co-worker's Chiral P,N-Ligands 227a-f (1 999)

Reagents and conditions: (a) 2-hydroxyphenylboronic acid, Pd(PPh&, Na2C03, dioxanelH20

(6:l); (b) Tf20, 2,6-lutidine; (c) HPOPh2, Pd(OAc),, dppb, i-Pr2NEt, DMSO; (d) HSiC13, NEt3,

PhCH3.

In 2001, synthetic routes to the terpene-derived P,N-ligand 232 were reported

1 independently by KoEovskL and co-workers and Chelucci and c o - w o r k e r ~ . ~ ~ ~ ~ ~ Each

/synthetic route used the Krohnke cyclization reaction to install the pyridine ring by

I

'(97) Malkov, A. V.; Bella, M.; Starl, G.; Kofovsk~, P. Modular Pyridine-Type P,N-Ligands Derived horn

Monoterpenes: Application in Asymmetric Heck Addition. Tetrahedron Lett. 2001,42, 3045.

(98) Chelucci, G.; Saba, A.; Soccolini, F. Chiral 2-(2-Diphenylphosphinopheny1)-5,6,7,8-

tl etrahydroquinolines: New P,N-Ligands for Asymmetric Catalysis. Tetrahedron 2 001, 57,9989.

reaction of the terpene derived a$-unsaturated ketone 230 with the pyridinium salts 229

or 234. The major difference between the two synthetic routes that were described was in

the way in which the diphenylphosphino moiety was installed. In the route reported by

KoEovsk9, a nucleophilic displacement of the aromatic fluoride 231 with potassium

diphenylphosphide was used to afford the chiral nonracemic P&-ligand 232 in 49% yield

(Scheme 1.12.3.).

Scheme 1.12.3. KoCovsky and Co-worker's Terpene-Derived P,N-Ligand 232 (2002)

231 232

Reagents and conditions: (a) I*, pyridine; (b) NH,OAc, AcOH, 90 "C, 3 h, 47%; (c) KPPh,, 18-

crown-6, THF, room temperature, 48 h, 49%.

The route described by Chelucci featured a nickel(I1)-catalyzed coupling reaction

between the aromatic triflate 236 and diphenylphosphine in the presence of 1,4-

diazabicyclo[2.2.2]octane (DABCO) that afforded the desired P,N-ligand 232 in 43%

yield (Scheme 1.12.4.).

Scheme 1.12.4. Chelucci and Co-worker's Terpene-derived P,N-Ligand 232 (2002)

Reagents and conditions: (a) 12, pyridine; (b) NH40Ac, AcOH, 100 "C, 4 h, 24%; (c) BBr3, CH2CI2,

86%; (d) Tf20, pyridine, CH2CI2, 82%; (e) HPPh2, 10 mol % of NiCI2(dppe), DABCO (2 equiv),

DMF, 100 "C, 43%.

1.12.2. Chiral Pyridylphosphine Ligands With Axial Chirality

To date, there have only been a few syntheses of pyridylphosphine ligands

reported which contain axial chirality. In 1998, Dai and co-workers reported the

synthesis of the atropisorneric quinazolinone P,N-ligand (9-241 (Scheme 1.12.5.).~~ The

starting material employed was (~-2-methyl-3-(2-diphenylphosphino-6-methylphenyl)-

4(3H)-quinazolinone (S)-239. This compound was prepared in racemic form by

condensation of N-acetylanthranillic acid 237 and 2-(dipheny1phosphino)-6-methylaniline

238. The atropisomers were then resolved by coordination of this phosphine to a chiral

(99) (a) Dai, X.; Wong, A.; Virgil, S. Synthesis and Resolution of Quinazolinone Atropisomeric Phosphine

Ligands. J. Org. Chem. 1998, 63, 2597. (b) Dai, X.; Virgil, S. Asymmetric Allylic Alkylation by

Palladium Complexes with Atropisomeric Quinazolinonc Phosphine Ligands. Tetrahedron Lett. 1999, 40,

1245.

palladium complex and subsequent fractional crystallization. The methyl group of the

product (9-239 was then deprotonated with n-butyllithium in tetrahydrofuran and the

resultant anion was reacted with 2-pyridinecarboxaldehyde to afford, after aqueous

workup, the unsaturated P,N-ligand (E,S)-240. The saturated P,N-ligand (9-241 was

obtained following a hydrogenation reaction.

Scheme 1.12.5. Dai and Co-worker's Axially Chiral Quinazolinone P,N-Ligands 240 and 241

(1 998)

a b

NHAc PPh2

(E, S)-240 y-J

Reagents and conditions: (a) PhS02CI, DMAP, pyridine, benzene, 80 OC, 36 h, 77%, then

resolution of atropisomers; (b) n-BuLi, THF, -78 "C then 2-pyridinecarboxaldehyde, 78%; (b) H2,

10% Pd/C, 95%.

In 1999, Zhang and co-workers reported the synthesis of two axially chiral P,N-

ligands (9-243 which contained a 1,l '-binapthalene backbone (Scheme 1.1 2.6.).Io0 The

ligands were prepared from the known aminophosphine (9-242 by reaction with 2-

pyridinecarboxylic acid or 6-methyl-2-pyridinecarboxylic acid in the presence of the

(100) Hu, W.; Chen, C.-C.; Zhang, X. Development of New Chiral P,N Ligands and Their Application in

the Cu-Catalyzed Conjugate Addition of Diethylzinc to Enones. Angew. Chem., Int. Ed. 1999, 38,35 18.

coupling reagents N,N'-dicyclohexylcarbodiimide and Nfl-dimethyl-4-aminopyridine in

dichloromethane.

Scheme 1 .l2.6. Zhang and Co-worker's Axially Chiral P,N-Ligand 243 (1 999)

(S)-242 (S)-243a, b

Reagents and condifions: (a) N,N-dicyclohexylcarbodiimide, DMAP, 2-pyrdinecarboxylic acid or

6-methyl-2-pyridine carboxylic acid.

1.12.3. Chiral Pyridylphosphine Ligands with Planar Chirality

In 2002, Fu and co-workers reported the synthesis of the novel planar chiral P,N-

ligand 246 (Scheme 1.12.7.).1•‹' The synthesis began by sequential treatment of iron(I1)

chloride with Cp*Li and then the anion obtained on deprotonation of 2-chloro-4-methyl-

pyrindine 157 with n-butyllithium which afforded the racemic planar chiral 2-

chloropyridine 158. A nickel(I1)-catalyzed coupling reaction of the 2-chloropyridine 158

with methylmagnesium bromide afforded the 2-methylpyridine 245. Regioselective

deprotonation of the 2-methyl group with n-butyllithium followed by reaction with

chlorodiphenylphosphine afforded the desired planar chiral P,N-ligand 246 which was

resolved by chiral HPLC.

(101) Tao, B.; Fu, G. C. Application of a New Family of P,N-Ligands to the Highly Enantioselective

Hydrosilylation of Aryl Alkyl and Dialkyl Ketones. Angew. Chem., Int. Ed. 2002,41, 3892.

Scheme 1.12.7. Fu and Co-worker's Planar Chiral P,N-Ligand 246 (2002)

Reagents and conditions: MeMgBr, NiC12(dppp), 80%; (b) n-BuLi then CIPPh2, 71%.

The application of some of the chiral pyridylphosphine ligands described above in

palladium-catalyzed asymmetric allylic substitution reactions and palladium-catalyzed

asymmetric Heck reactions is reviewed in the following sections.

1.12.4. Catalytic Asymmetric Allylic Substitution Reactions

The palladium-catalyzed asymmetric allylic substitution (AM) reaction involves

the displacement of an allylic leaving group with a nucleophile (Scheme 1. 12.8.).lo2 This

reaction has received a great deal of attention due to its synthetic versatility which is

demonstrated by its extensive application in target-oriented synthesis.lo3

Scheme 1.12.8. Palladium-Catalyzed Asymmetric Allylic Substitution Reaction

Palladium Catalyst Nu

R NU * R

(102) For reviews on the AAS reaction, see: (a) Trost, B. M. Asymmetric Allylic Alkylation, an Enabling

Methodology. J. Org. Chern. 2004, 69, 5813. (b) Trost, B. M. Pd Asymmetric Allylic Alkylation (AAA).

A Powerful Synthetic Tool. Chern. Pharrn. Bull. 2002, 50, 1. (c) Trost, B. M.; Van Vranken, D. L.

Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chern. Rev. 1996, 96, 395.

(103) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:

Applications in Total Synthesis. Chern. Rev. 2003, 103,2921.

The proposed mechanism of the AAS reaction is shown below (Figure 1.12.1.).

In the first step, the allylic substrate 247 undergoes coordination to the palladium catalyst

252 to form the x-complex 249. Subsequent oxidative addition of the palladium centre to

the C-X bond with inversion of configuration generates the cationic (x-ally1)palladium

intermediates W-250 and M-250. These intermediates are in conformational equilibrium

and have been observed spectroscopically104 and crystallographically.105 A nucleophile

then attacks these electrophilic intermediates and displaces the palladium with inversion

of configuration to generate complex 251. In the final step of the mechanism, the

reaction product 248 is decomplexed from the palladium catalyst. This mechanism only

holds for nucleophiles with a pKa that is less than 25. Nucleophiles with a pKa that is

greater than 25 undergo an alternative reaction pathway that involves coordination of the

nucleophile to the palladium centre followed by a reductive elimination process.

(104) Moberg, C.; Brember, U.; Hallman, K.; Svensson, M.; Norrby, P.; Hallberg, A.; Larhed, M.;

Csoregh, I. Selectivity and Reactivity in Asymmetric Allylic Alkylation. Pure Appl. Chem. 1999, 71, 1477.

(105) Sauthier, N.; Fornies, J.; Toupet, L.; Reau, R. Palladium(l1) Complexes of Chiral 1,2-

Diiminophosphoranes: Synthesis, Structural Characterization, and Catalytic Activity for the Allylic

Alkylation. Organometallics 2000, 19, 553.

248

Decomplexation

Nucleophilic Addition Q J Ionization

Figure 1.12.1. Mechanism for palladium-catalyzed allylic substitution reactions.

An important aspect of this proposed mechanism is that the cationic (n-

ally1)palladium complex exists in a dynamic equilibrium during which its conformation

and structure may change by dissociation and reassociation p r o c e s s e s . ' O ~ n the above

mechanism, only the M- and W-isomers of the cationic (n-ally1)palladium complex are

shown. However, it is important to note that the anti,syn isomers are also possible via

isomerization of both the M- and W-isomers (Figure 1.12.2.).

Figure 1.12.2. Dynamic conformational equilibria of cationic rr-allyl metal complexes.

(106) Trost, B. M.; Toste, F. D. Regio- and Enantioselective Aliylic Alkylation of an Unsymmetrical

Substratc: A Working Model. J. Ani. Chetn. Soc. 1999, 121,4545.

The benchmark reaction for evaluating new chiral ligands in the AAS reaction is

the palladium-catalyzed nucleophilic attack of the anion of dimethyl malonate 254 on

racemic 1,3-diphenylprop-2-enyl acetate vac-253 (Scheme 1.12.9.). This reaction is

typically performed by coordinating the chiral ligand to allylpalladiumchloride dimer in

situ followed by the addition of dimethyl malonate, N,O-bistrimethylsilyl acetamide

(BSA) and a catalytic amount of potassium acetate (Trost's procedure).'07

Scheme 1.12.9. Palladium-Catalyzed Asymmetric Allylic Substitution Reaction of Racemic 1,3-

Diphenylprop-2-enyl acetate rac-253 with Dimethyl Malonate 254

+ BSA, KOAc (cat.) w Ph

rac-253 Ph

255

The palladium complexes of the chiral 2-(phosphinoary1)pyridine ligands 227a-f

reported by Kastsuki and co-workers were evaluated in this reaction using Trost's

procedure.97 Each of the ligands afforded the product 255 in less than three hours at

room temperature and in high yields. The enantioselectivities ranged from good to

excellent (64 to 97% ee). The best result was obtained with ligand 227b which showed a

very high catalytic activity (reaction time -30 min) and afforded the product in excellent

enantiomeric excess (97%).

The terpene-derived P,N-ligands 232 reported by Chelucci and KoEovsky have

also been evaluated using Trost's procedure.'8~99 The ligands provided a high degree of

(107) Trost, B. M.; Murphy, D. J. A Model for Metal-Templated Catalytic Asymmetric Synthesis via n-

Ally1 Fragments. Organometallics 1985, 4, 1143.

catalytic activity and afforded the product 255 in high yield. The enantioselectivities

observed were moderate to good in these reactions (37 to 70% ee).

The axially chiral ligands (8-240 and (9-241 reported by Dai and co-workers

have been evaluated in the allylic substitution reaction under a variety of condition^.'^^

The optimal conditions involved the use of sodium hydride as the base in the presence of

15-crown-5 in dichloromethane. Under these conditions the product 255 was obtained in

good enantiomeric excess (85%) with the unsaturated ligand (8-240 and in lower

enantiomeric excess (78%) with the saturated ligand (9-241. This suggested that the

palladium-complex formed with the saturated ligand (8-241 is less conformationally

rigid and that this resulted in a loss of stereoselectivity.

1.12.5. Catalytic Asymmetric Heck Reaction

The palladium-catalyzed Heck reaction is a particularly versatile carbon-carbon

bond formation reaction in organic synthesis.lo8 The overall reaction involves the

coupling of an aryl (or vinyl) halide or triflate 257 with an alkene substrate 256 (Scheme

Scheme 1.12.10 Palladium-Catalyzed Heck Reaction

Pd-catalyst, base, A

R 4 + Ar-X w

+ ~ r

256 257 (X = CI, Br, I or OTf) 258

(108) For a review on the Heck reaction, see: Shibasaki, M.; Vogl, E. M.; Ohshima, T. Asymmetric Heck

Reaction. Adv. Synth. Catal. 2004, 346, 1533.

The first examples of asymmetric Heck reactions were reported independently in

1989 by Shibasaki and co-workers and Overman and co-workers (Figure 1.12.3.). 109,110

Here, the achiral vinyl iodide 259 and triflate 261 underwent asymmetric intramolecular

cyclization reactions to afford the products 260 and 262, respectively. Although the

enantioselectivities achieved in these initial reactions were only moderate (45 to 46% ee),

the potential of this reaction as a powerful asymmetric carbon-carbon bond formation

reaction was clearly demonstrated.

Shibasaki and co-workers

3 rnol % Pd(OAch, 9 mol % (R)-BINAP 26, C02Me

Ag2C03, NMP, 60 "C

74% * H

259 260 (46% ee)

Overman and co-workers

10 rnol % P~(OAC)~ , 10 rnol % (R,R)-DIOP 19,

Et3N, benzene, room temperature

90% 0 * $ 0

261 262 (45% ee)

Figure 1.12.3. Asymmetric Heck reactions reported by Shibasaki and co-workers and Overman

and co-workers (1 989).

(109) Sato, Y.; Sodeoka, M.; Shibasaki, M. Catalytic Asymmetric Carbon-Carbon Bond Formation:

Asymmetric Synthesis of cis-Decalin Derivatives by Palladium-Catalyzed Cyclization of Prochiral Alkenyl

Iodides. J. Org. Chem. 1989,54,4738.

(1 10) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. Palladium-Catalyzed Polyene Cyclizations of Trienyl

Triflates. J. Org. Chem. 1989, 54, 5846.

Recently, Pfaltz and co-workers have shown the effectiveness of chiral P,N-

ligands, particularly phosphinooxazolines 266, in catalytic asymmetric Heck reactions."'

High enantioselectivities (up to 97% ee) were observed in the asymmetric Heck reaction

of phenyl triflate 263 with 2,3-dihydrofuran 264 (Scheme 1.12.1 1 .).

Scheme 1.12.1 1. Palladium-Catalyzed Asymmetric Heck Reaction

PhOTf 263 3 mol % Pd(dbah 6 mol % L* 266 (R = t-Bu)

THF, (i-Pr)2NEt, 70 O C , 4 days {O ' y p h

265 (97% ee)

The chiral pyridylphosphine ligands 232 reported by Kotiovsky and co-workers

have also been evaluated in the asymmetric Heck reaction of phenyltriflate and

dihydrohran. In this case, the reaction product was isolated in moderate to good

enantiomeric excess (up to 7 0 % ) . ~ ~ This is the only report in the literature of a chiral

pyridylphosphine ligand being evaluated in a catalytic asymmetric Heck reaction.

1 .l3. Thesis Overview

In Chapter 2 of this thesis, the synthesis of a series of chiral nonracemic C2-

symmetric 2,2'-bipyridyl ligands is described. These ligands were evaluated as chiral

directors in copper(1)-catalyzed asymmetric cyclopropanation reactions of alkenes and

diazoesters.

(1 11) For a review on the use of chiral phosphinooxazoline ligands in the asymmetric Heck reaction, see:

Loiseleur, 0.; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz, A. J. Organomet. Chem. 1999, 576, 16.

In Chapter 3, the synthesis of a related chiral nonracemic pyridine N-oxide as well

as a C2-symmetric 2,2'-bipyridine N,N'-dioxide is described. These N-oxides were

evaluated as catalysts in a desymmeterization reaction of cis-stilbene oxide.

In Chapter 4, the synthesis of a series of chiral nonracemic pyridylphosphine

ligands is described. These ligands were constructed based on the same design concept

that was used for the 2,2'-bipyridine ligands and the N-oxides. These P,N-ligands were

then evaluated for use as chiral directors in palladium-catalyzed asymmetric Heck

reactions, in palladium(I1)-catalyzed asymmetric allylic substitution reactions and in

iridium(1)-catalyzed asymmetric hydrogenation reactions.

In Chapter 5, the synthesis of a chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligand that originated from a subtle modification of the 2,2'-bipyridyl ligands, described

in Chapter 2, is described. This ligand was evaluated in copper(1)-catalyzed asymmetric

cyclopropanation reactions of alkenes and diazoesters, in copper(I1)-catalyzed

asymmetric Friedel-Crafts alkylation reactions and in copper(1)-catalyzed asymmetric

allylic oxidation reactions.

In Chapter 6, an outline of the future development of this research project in

asymmetric synthesis is outlined and in Chapter 7, an overall conclusion section on the

research described in this thesis is presented.

In the final chapter of this thesis, Chapter 8, the experimental procedures and full

characterization data (including elemental analyses or high-resolution mass spectrometry)

concerning all of the compounds discussed in this thesis are provided.


SYNTHESIS AND EVALUATION OF A SERIES OF NEW CHIRAL NONRACEMIC C2-SYMMETRIC AND

UNSYMmTRIC 2,2 '-BIPYRIDYL LIGANDS

2.1. Introduction

In this chapter, a modular synthesis of a series of new chiral nonracemic and C2-

symmetric 2,2'-bipyridyl ligands as well as the synthesis of the corresponding

unsymmetric 2,2'-bipyridyl ligands is described. The design concept that was conceived

for the construction of these new 2,2'-bipyridyl ligands was discussed earlier in this

thesis (Chapter 1, Section 1.8.).* The objective of this research project was to evaluate

the effect of the chiral cyclic acetal substituent of these ligands in various catalytic

asymmetric reactions.

We envisioned modular syntheses of the C2-symmetric 2,2'-bipyridyl ligands

267a-c (R = Me, i-Pr and Ph) via condensation of the chloroketone 269 and the

corresponding chiral nonracemic C2-symmetric 1,2-diols 270a-c. The resultant chiral

acetals 268a-c would then be converted to the C2-symmetric ligands 267a-c by a

nickel(0)-mediated homo-coupling reaction (Figure 2.1.1 .). In this manner, a series of

ligands could potentially be prepared from a common intermediate (the chloroketone

269). Moreover, the substitution pattern of the chiral acetal could be varied by selection

of an appropriate 1,2-diol so that the ligand could be modified for optimization in a

particular asymmetric reaction. The methyl substituent at C-4 of these ligands was

(*) Part of the research described in this Chapter has been submitted for publication: Lyle, M. P. A.;

Draper, N. D.; Wilson, P. D. Synthesis and Evaluation of New Chiral Nonracemic C2-Symmetric and

Unsymmetric 2,2'-Bipyridyl Ligands. J. Org. Chem. 2005, 70,0000.

selected to facilitate the synthesis of the heterocyclic precursors from readily available

starting materials.

267a-c (R = Me, i-Pr and Ph) 268a-c (R = Me, i-Pr and Ph)

Figure 2.1.1. Retrosynthetic analysis of the chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligands 267a-c (R = Me, i-Pr and Ph).

In a similar fashion, the chiral nonracemic unsyrnmetric 2,2'-bipyridyl ligands

271a-c (R = Me, i-Pr and Ph) could be prepared by a Stille coupling reaction of the chiral

acetals 268a-c (R = Me, i-Pr and Ph) and the known 2-(tri-n-butylstanny1)pyridine 272

(Figure 2.1 .2.).54

271a-c (R = Me, i-Pr and Ph) 268a-c (R = Me, i-Pr and Ph) 272

Figure 2.1.2. Retrosynthetic analysis of the chiral nonracemic unsyrnmetric 2,2'-bipyridyl ligands


2.2. Chiral Nonracemic C2-Symmetric 1,2-Diols (270a-c)

A variety of chiral nonracemic C2-symmetric diols are commercially available or

can be readily prepared from achiral or chiral nonracemic precursors. For our

investigations, we selected three C2-symmetric 1,2-diols that would provide a series of

bipyridine ligands with varying steric properties around the binding site of the chiral

ligands. These were: (2R,3R)-2,3-butanediol 270a (R = Me); (1S,2S)-1,2-diisopropyl-

1,2-ethanediol 270b (R = i-Pr); and (1S,2S)- 1,2-diphenyl- l,2-ethanediol 270c (R = Ph)

(Figure 2.2.1 .).

(R, R)-270a (S,S)-270b (S, S)-270c

Figure 2.2.1. Chiral nonracemic C2-symmetric 1,2-diols 270a-c.

Of the three chiral diols, the diols 270a (R = Me) and 270c (R = Ph) are currently

commercially available in both enantiomeric forms.* However, when this research

project was initiated, the chiral diol270c (R = Ph) was not commercially available and so

it was prepared on a large scale via the Sharpless asymmetric dihydroxylation reaction of

(E)-stilbene 273 (Scheme 2.2.1 .).I l2 This involved the reaction of (E)-stilbene 273 and

AD-mix$ in a mixture of tert-butanol and water (1:l) at 0 O C for 24 h that afforded the

desired chiral nonracemic diol 270c (R = Ph) in good yield (82%) and in high

enantiomeric excess (>99%) after a single recrystallization from ether. The enantiomeric

(*) (2R,3R)-2,3-Butanediol is significantly less expensive than the corresponding (2S,3S)-enantiomer and

so it was purchased for use in these studies.

(1 12) Sharpless, K.; Amberg, Y.; Bannani, G.; Crispino, J.; Hartung, K.; Jeong, H.; Kwong, K.; Morikawa,

Z.; Wang, D. Xu, X.; Zhang, X.-L. The Osmium-Catalyzed Asymmetric Dihydroxylation: A New Ligand

Class and a Process Improvement. J. Org. Chem. 1992,57,2768.

purity of the diol270c was determined by comparison of the optical rotation ([a] g - 94.0

[ c 2.5, ethanol]) with a literature value ([a] - 94.1 [c 1.0, ethanol]).'13

Scheme 2.2.1. Preparation of the Chiral Nonracemic 1,2-Diol 270c (R = Ph) via a Sharpless

Asymmetric Dihydroxylation Reaction

273 270c (>99% ee)

The non-commercially available diol 270b (R = i-Pr) was synthesized from

(2R,3R)-(+)-tartaric acid ethyl ester 274 according to a five-step literature procedure

(Scheme 2.2.2.).'14 The first step of the sequence involved the reaction of (2R,3R)-(+)-

tartaric acid ethyl ester 274 with cylcopentanone in the presence of a catalytic amount of

p-toluenesulfonic acid in benzene at reflux for 3 days which afforded the acetal 275 in

good yield (91%). The acetal 275 was then reacted with four equivalents of methyl

magnesium bromide in tetrahydrofuran at 0 O C to afford the diol276 in good yield (89%).

The dimesylate was then prepared on treatment of the diol 276 with excess

methanesulfonyl chloride in dichloromethane in the presence of triethylamine and N,N-

dimethyl-4-aminopyridine at 0 O C for 30 min. After removal of the volatiles, the crude

dimesylate was taken up in dimethyl sulfoxide and treated with potassium tert-butoxide

at room temperature for 16 h to afford the diene 277 in good yield (55%, over two steps).

(1 13) Prasad, K. R. K.; Joshi, N. N. Stereoselective Reduction of Benzils: A New Convenient Route to

Enantiomerically Pure 1,2-Diarylethanediols. J. Org. Chem. 1996, 61, 3888.

(1 14) (a) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. Enantioselective Complexation of Organic

Ammonium Ions By Simple Tetracyclic Podand Ionophores. J. Am. Chem. Soc. 1992, 114, 4128. (b)

Matteson, D. S.; Beedle, E. C.; Kandil, A. A. Preparation of (3S,4,!+2,5-Dimethyl-3,4-hexane diol [(S)-

DIPED] from (R,R)-Tartaric Acid via Trimethylsilyl Chloride Catalyzed Acetylation of a Hindered 1,4-

Diol. J. Org. Chem. 1987, 52, 5034.

The diene was then reduced using a Raney nickel-catalyzed hydrogenation reaction (40

psi Hz) in ethanol to afford the acetal 278 in excellent yield (95%). The acetal 278 was

then hydrolyzed with aqueous hydrochloric acid (2 M) in tetrahydrofuran at room

temperature that afforded the desired chiral diol 270b (R = i-Pr) in good yield (87%).

This synthetic procedure was performed on a large scale that allowed for the preparation

of multi-gram quantities of this diol.

Scheme 2.2.2. Synthesis of (1 S,2S)-1,2-Diisopropyl-I ,2-ethanediol 270b

Reagents and Condjtjons: (a) cyclopentanone, p-TsOH (cat.), benzene, reflux, 3 days, 91%; (b)

MeMgBr, THF, 0 "C, 3 h, 89%; (c) MsCI, DMAP, Et3N, CH2CI2, 0 "C, 30 min, volatiles removed

then; KOt-Bu, DMSO, room temperature, 16 h, 55% (over two steps); (d) Raney-Ni, Hz (40 psi),

EtOH, 95%; (e) HCI (2 M aq), THF, room temperature, 3 days, 87%.

2.3. Synthesis of the Chloroketone (269)

The synthesis of the chloroketone 269 was accomplished in six steps from the

known 2-hydroxypyridine 280 (Scheme 2.3.l.).'I5 The 2-hydroxypyridine 280 was

prepared on a multi-gram scale by heating equimolar amounts of cyclopentanone, ethyl

acetoacetate and ammonium acetate at reflux for 8 hours. The crystalline product that

was precipitated from the crude reaction mixture was subsequently recrystallized from

ethanol to afford the 2-hydroxypyridine 280 in 23% yield. The relatively low yield of

this reaction does not take away from the overall efficiency of the synthetic route as it is

the first step in the sequence. Moreover, the reaction was performed on a large scale and

inexpensive starting materials were employed. The IR spectrum of the 2-

hydroxypyridine 280 had a characteristic broad 0-H peak at 2912 cm". Moreover, in the

1 H NMR spectrum, the C-3 aromatic proton resonance appeared at 8 = 6.22 ppm which

indicated that the 2-hydroxypyridine 280 existed mainly as the aromatic tautomer. The

first attempt at the conversion of the 2-hydroxypyridine 280 to the 2-chloropyridine 281

involved heating the 2-hydroxypyridine 280 in phosphoryl chloride at reflux (bp. 106 OC)

for 24 hours. However, in this instance only starting material was recovered.ll6 It was

subsequently inferred that the chlorination reaction needed to be run at a higher

temperature. In order to avoid the need to repeat this reaction in a sealed-tube,

phenylphosphonic dichloride was selected as an alternative chlorinating agent. This

substance has a relatively high boiling point (bp. 258 "C). Accordingly, the 2-

(1 15) Sakurai, A.; Midorikawa, H. The Cyclization of Ethyl Acetoacetate and Ketones by Ammonium

Acetate. Bull. Chem. Soc. Jpn. 1968, 41, 165.

(1 16) Ruble, J. C.; Fu, G. C. Chiral z-Complexes of Heterocycles with Transition Metals: A Versatile New

Family of Nucleophilic Catalysts. J. Org. Chem. 1996, 61,7230.

hydroxypyridine 280 was heated at 160 OC with phenylphosphonic dichloride for 16 h

which afforded the 2-chloropyridine 281 in good yield (83%).Il7 The mass spectrum of

this compound displayed molecular ion peaks for M ( ~ ~ c ~ ) and M ( ~ ~ c ~ ) in a 3:l ratio

which is diagnostic of the incorporation of a chlorine atom. Subsequent oxidation of this

compound with 30% aqueous hydrogen peroxide in acetic acid at 80 "C for 16 hours

afforded the corresponding pyridine N-oxide. This compound was then heated with

acetic anhydride at 100 OC to afford the acetate 282 in good yield (60%, over two

steps).11s Hydrolysis of the acetate 282 with lithium hydroxide in a mixture of

tetrahydrofuran and water (3:l) at room temperature for 4 hours afforded the

corresponding alcohol 283 in excellent yield (94%). Subsequent Swern oxidation

afforded the desired chloroketone 269 in high yield (90%).l19 The IR spectrum of the

chloroketone 269 displayed a characteristic carbonyl peak at 1714 cm-' and a resonance

for the carbonyl carbon at 6 = 203.7 ppm was observed in the 13c NMR spectrum.

(1 17) Robison, M. M. The Preparation of IJ-Pyrindene. J. Am. Chem. Soc. 1958, 80, 6254.

(1 18) The synthesis of the acetate 282 by similar methods has been reported by Fu and co-workers, see:

Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C. Synthesis, Resolution and Crystallographic Characterication of

a New C2-Symmetric Planar-Chiral Bipyridine Ligand: Application to the Catalytic Enantioselective

Cyclopropanation of Olefins. Chem. Commun. 2000,377.

(1 19) Mancuso, A. J.; Huang, S. L.; Swern, D. Oxidation of Long Chain and Related Alcohols to Carbonyls

by Dimethyl Sulfoxide "Activated" by Oxalyl Chloride. J. Org. Chem. 1978, 43, 2480.

Scheme 2.3.1. Synthesis of the Chloroketone 269

Reagents and Conditions: (a) ethyl acetoacetate, NH40Ac, reflux, 8 h, 23%; (b) PhP(O)CI2, 160

"C, 16 h, 83%; (c) H202, H20, AcOH, 80 "C, 16 h; (d) Ac20, room temperature, 1 h then 100 "C, 4

h, 60% (over two steps); (e) LiOH, THF, H20, room temperature, 16 h, 94%; (f) (COCI),, DMSO,

CH2CI2; NEt3, -78 "C to rt, 90%.

The N-oxide acetylation/migration sequence, employed in this synthetic route, is

referred to as the "Boekelheide reaction" and it is formally a [3.3]-sigmatropic

rearrangement of the acetylated N-oxide. This reaction provides a useful method for

functionalization of the benzylic position of 2-alkylpyridines (Figure 2.3.1 .).I2' In the

proposed mechanism, the acetylated pyridine N-oxide 284 is deprotonated with acetate

ion to afford the non-aromatic acetylated N-oxide 285. This intermediate then undergoes

a [3.3]-sigmatropic rearrangement to afford the acetate 282.12'

(120) (a) Katada, M. J. Phat-m. Soc. Jpn. 1947, 67, 51. (b) Boekelheide, V.; Linn, W. J. Rearrangements of

N-Oxides. A Novel Synthesis of Pyridyl Carbinols and Aldehydes. J. Am. Chem. Soc. 1954, 76, 1286.

(121) Oae, S.; Tamagaki, S.; Negoro, T.; Ogino, K.; Kozuka, S. Kinetic Studies on the Reactions of 2- and

4-Alkyl-Substituted Heteroaromatic N-Oxides with Acetic Anhydride. Tetrahedron Lett. 1968,917.

Figure 2.3.1. Mechanism for the Boekelheide reaction used for the preparation of the acetate

282.

2.4. Synthesis of the Chiral Nonracemic Cyclic Acetals (268a-c)

The chiral acetals 268a-c (R = Me, i-Pr and Ph) were prepared in good yield on

condensation of the chloroketone 269 with the corresponding chiral nonracemic C2-

symmetric 1,2-diols 270a-c on heating at reflux in benzene in the presence of a catalytic

amount of p-toluenesulfonic acid (Scheme 2.4.1.).* These compounds were fully

characterized by spectroscopic means and gave satisfactory elemental analyses.

(*) The reactions of the 2-chloroketone 269 with the chiral diols 270a-c proceeded smoothly in the

presence of 15 mol % of p-toluenesulfonic acid monohydrate. In our experience, related ketones that do

not possess the 2-chloro substituent have required greater than one equivalent of an acid catalyst (see: ref.

53). Thus, it appears that the electron withdrawing chlorine atom lowers the basicity of the pyridine

nitrogen relative to non-chlorinated pyridines.

Scheme 2.4.1. Synthesis of the Chiral Nonracemic Acetals 268a-c

Me,

269 270a-c (R = ~ e ' , i-Pr and Ph) 268a-c (R = ~ e * , i-Pr and Ph)

Reagents and Conditions: (a) 1,2-diols 270a-c (R = Me, i-Pr and Ph), p-TsOH (cat.), benzene,

* reflux, 16 h, 85% (268a), 89% (268b), 79% (268~). The compound used in this study was the

enantiomer of that indicated in the reaction scheme.


Ligands [267a-c (R = Me, i-Pr and Ph)]

The acetals 268a-c were converted to the chiral nonracemic C2-symmetric 2,2'-

bipyridyl ligands 267a-c by a nickel(0)-mediated homo-coupling reaction upon heating in

tetrahydrofuran with dibromobis(triphenylphosphine)nickel(II), tetraethylammonium

iodide and zinc The reactions of the chiral acetals 268b (R = i-Pr) and 268c (R =

Ph) both afforded the corresponding 2,2'-bipyridyl ligand in good yield (72% and 73%,

respectively). However, in the case of the reaction of the chiral acetal 268a (R = Me), a

significant amount of the reductively dehalogenated product 286a (35%) was obtained

along with the desired 2,2'-bipyridyl ligand (41%) (Scheme 2.5.1 .).

(122) (a) Dehmlow, E. V.; Sleegers, A. Synthesis of Unsymmetrically and Symmetrically Structured

Dihydroxybipyridines. Liebigs Ann. Chem. 1992, 953. (b) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.;

Oda, M. Homocoupling of Aryl Halides using Nickel(I1) Complex and Zinc in the Presence of EtdNI. An

Efficient Method for the Synthesis of Biaryls and Bipyridines. Bull. Chem. Soc. Jpn. 1990, 63, 80.

Scheme 2.5.1. Synthesis of the C2-Symmetric 2,2'-Bipyridyl Ligands 267a-c

268a-c (R = Me', i-Pr and Ph) 1 286a (R = Me')

267a-c (R = ~ e ' , i-Pr and Ph)

Reagents and conditions: (a) NiBr2(PPh&, Zn dust, Et4NI, THF, 60 OC, 4 days, 41% (267a), and

35% (286a), 72% (267b), 79% (267~) . The compound used in this study was the enantiomer of

that indicated in the reaction scheme.

The structures of the products isolated from the above homo-coupling reactions

were confirmed on the basis of spectroscopic evidence. In particular, the mass spectra of

the 2,2'-bipyridyl ligands 267a-c each showed the expected molecular ion peaks for

M(267a + H) at 437, for M(267b + H) at 550 and for M(267c + H) at 686, respectively.

The 'H NMR spectra for each of the C2-symmetric 2,2'-bipyridyl ligands 267a-c

(R = Me, i-Pr and Ph) is shown below (Figure 2.5.1.). Of note, the distinct chemical

environment of the two diastereotopic faces of these molecules was indicated by the

proton signals of the chiral cyclic acetal moieties. The signal for the interior hydrogen

(A) is shifted downfield with respect to the signal for the exterior hydrogen (B). This

results from the proximity of the interior proton to the aromatic n-system of the pyridine

moiety. In addition, the relative simplicity of the 'H NMR spectra clearly indicated the

C2-symmetry of the ligands.

1 Figure 2.5.1. H NMR spectra of the C2-symmetric 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr

Ph).

The 13c NMR spectra for each of the 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr

and Ph) is shown below (Figure 2.5.2.). The simplicity of the 13c NMR spectra further

indicated the C2-symmetry of these molecules. For instance, the 13c NMR spectrum of

the 2,2'-bipyridyl ligand 267a (R = Me), which has a molecular formula of Cz6H32N204,

displayed thirteen signals.

Figure 2.5.2. 13c NMR spectra of the C2-symmetric 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr

Ph).

The reductively dehalogenated product 286a was assigned based upon the mass

spectrum which displayed a molecular ion peak for M(286a + H) at 220 and the 'H NMR

spectrum which displayed C-2 and C-3 aromatic proton resonances as doublets with

identical coupling constants (J = 4.9 Hz) at 6 = 7.00 ppm and 6 = 8.40 ppm (Figure

2.5.3.).

p OY 'Me

Me

Figure 2.5.3. 'H NMR spectrum of the reductiveiy dehalogenated product 286a.

The formation of a significant quantity of the reductively dehalogenated product

286a in the nickel(0)-mediated homo-coupling reaction of the 2-chloroacetal 268a (R =

Me) was problematic because it occurred in the last step of the synthetic sequence after

the valuable chiral portion of the molecule had been installed. In order to circumvent this

problem, it was decided to prepare the corresponding 2-bromoacetal 291a (R = Me)

(Scheme 2.5.2.). Here, it was considered that the increased reactivity of the pyridyl-

bromide bond would lead to a higher yield of the desired 2,2'-bipyridine ligand 267a (R

= Me). The lower reactivity of aryl-chloride bonds relative to aryl-bromide bonds in

metal-catalyzed coupling reactions is generally attributed to their reluctance to undergo

oxidative addition to the metal ~ a t a 1 ~ s t . l ~ ~ This is in agreement with the bond

dissociation energies for aryl halide bonds [at 298 K, Ph-Cl (96 kcal mol-') > Ph-Br (81

kcal mol-')I . 124

- - - -

(123) Grushin, V. V.; Alper, H. Transformation of Chloroarenes, Catalyzed by Transition-Metal

Complexes. Chem. Rev. 1994,94, 1047.

(124) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and OrganometalZic Compounds; Academic

Press: London, 1970.

The bromoacetal 291a was prepared in a similar fashion as to that used to prepare

the corresponding chloroacetal 268a (Scheme 2.5.2.). The 2-hydroxypyridine 280 was

converted in 52% yield to the 2-bromopyridine 287 upon heating at reflux in phosphorus

tribromide (bp. 175 "C). However, we found that the yield of this reaction was not

consistently reproducible and that the desired product was often isolated in much lower

yield. Moreover, the reaction was not particularly amenable to scale-up as emulsification

occurred during the work-up of the reaction mixture. The mass spectrum of the 2-

bromopyridine 287 showed molecular ion peaks for M(''B~) and M ( ~ ~ B ~ ) in a 1: 1 ratio

that confirmed the incorporation of a bromine atom. Treatment of the 2-bromopyridine

287 with 30% aqueous hydrogen peroxide in glacial acetic acid at 80 "C for 16 h afforded

the corresponding pyridine N-oxide. This compound was then heated in acetic anhydride

at 100 "C for 4 hours to afford the acetate 288 in good yield (54%, over two steps).

Hydrolysis of the acetate 288 with lithium hydroxide monohydrate in a mixture of

tetrahydrofuran and water (3: 1) at room temperature for 16 h then afforded the alcohol

289 in excellent yield (95%). Subsequent Swern oxidation afforded the bromoketone 290

in 90% yield. The IR spectrum of the bromoketone 290 displayed a strong and

characteristic carbonyl stretch at 17 18 cm" . Condensation of the bromoketone 290 with

(2R,3R)-2,3-butanediol 270a in the presence of a catalytic amount of p-toluenesulfonic

acid monohydrate in benzene at reflux afforded the bromoacetal 291a (R = Me) in high

yield (89%). The bromoacetal 291a (R = Me) was then subjected to the nickel(0)-

mediated homo-coupling reaction to afford the chiral2,2'-bipyridyl ligand 267a (R = Me)

in good yield (83%). In this case, as anticipated, none of the reductively dehalogenated

product 286a was detected.

Scheme 2.5.2. Synthesis of the 2,2'-Bipyridyl Ligand 267a from the 2-Bromopyridine 291

OAC

288 (R = Ac)

289 (R = H)

Reagents and Conditions: (a) PBr3, reflux, 12 h, 52%; (b) H202, H20, AcOH, 80 "C, 16 h; (c)

Ac20, rt, 1 h then 100 "C, 4 h, 54% (over two steps); (d) LiOH, THF, H20, rt, 16 h, 95%; (e)

(COCl)2, DMSO, CH2C12; NEt3, -78 "C to rt, 90%; (f) (2R,3R)-2,3-butanediol 270a, p-TsOH (cat.),

benzene, reflux, 20 h, 89%; (g) NiBr2(PPh3)2, Zn, EhNI, THF, 60 OC, 72 h, 83%.

The mechanism by which reduction of the aryl-chloride bond occurred in the case

of the acetal 268a (R = Me) is unclear. However, if this coupling reaction proceeds via

radical intermediates then the tetrahydrofuran reaction solvent or tetraethylammonium

iodide are the most likely sources of the hydrogen atoms as the reactions were performed

under strictly anhydrous conditions. The observation that this reductive process only

occurred during the homo-coupling reaction of the acetal268a (R = Me) can be attributed

to the fact that this less sterically encumbered molecule was more reactive than the

chloroacetals 268b (R = i-Pr) and 268c (R = Ph).

2.6. Synthesis of the Chiral Nonracemic Unsymmetric 2,2'-Bipyridyl

Ligands [271a (R = Me) and 271b (R = Ph)]

The unsymmetric 2,2'-bipyridyl ligands 271a (R = Me) and 271b (R = Ph) were

prepared from the chiral acetals 268a (R= Me) and 268c (R = Ph) by a palladium-

catalyzed Stille coupling reaction with 2-(ti-n-butylstanny1)pyridine 272 (Scheme

2.6.1 .).125,126 The chiral acetal268b (R = i-Pr) was not employed in this reaction because

of the relatively limited quantity of the chiral diol 270b at hand. It was found that the

chiral acetals 268a (R = Me) and 268b (R = Ph) reacted exceedingly slowly under

standard Stille coupling reaction conditions when tetrakis(tripheny1phosphine)

palladium(0) was employed as the catalyst on heating at reflux in benzene or toluene with

potassium carbonate as the base.127 However, the reactions proceeded smoothly upon

employment of the reaction conditions recently reported by Fu and co-workers to afford

the unsymmetric 2,2'-bipyridyl ligands 271a and 271b in good yield (72 and 83%,

respectively).128 These conditions involved heating a mixture of the acetal 268a (R =

Me) or 268b (R = Ph), the 2-(tri-n-butylstanny1)pyridine 272 and anhydrous cesium

fluoride in dioxane at reflux in the presence of catalytic amounts of

tris(dibenzylideneacetone)dipalladium(II) and tri-tert-butyl phosphine. From a practical

(125) Milstein, D.; Stille, J. K. A General, Selective and Fascile Method for Ketone Synthesis from Acid

Chlorides and Organotin Compounds Catalyzed by Palladium. J. Am. Chem. Soc. 1978,100,3636.

(126) For reviews on the Stille reaction, see: (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React.

1997, 50, 1. (b) Mitchell, T. N. In Metal Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,

Eds.; Wiley-VCH: New York, 1998, Chapter 4.

(127) Echavarren, A. M.; Stille, J. K. Palladium-Catalyzed Coupling of Aryltriflates with Organostannanes.

J. Am. Chem. Soc. 1987,109,5478.

(128) Littke, A. F.; Schwarz, L.; Fu, G. C. PdP(t-Bu),: A Mild and General Catalyst for Stille Reactions of

Aryl Chlorides and Aryl Bromides. J. Am. Chem. Soc. 2002,124,6343.

point of view, it is important to note that Stille coupling reactions are often plagued by

the difficulties in separating the desired reaction product from the trialkyltin halide

byproduct. This is not a problem under these conditions due to the in situ formation of

insoluble tri-n-butyltin fluoride.

Scheme 2.6.1. Synthesis of the Unsymmetric 2,2'-Bipyridyl Ligands 271a (R = Me) and 271 b (R

= Ph)

Me.

268a,c (R = Me*, Ph) 272 271a,b (R = Me*, Ph)

Reagents and Conditions: (a) 5 mol % Pd2dba3, 10 mol % P(~-Bu)~, CsF, dioxane, reflux, 24 h,

72% (271a), 83% (271b). The compound used in this study was the enantiomer of that

indicated in the reaction scheme.

The structure of the unsymmetric 2,2'-bipyridyl ligands 271a (R = Me) and 271b

(R = Ph) was confirmed on the basis of spectroscopic evidence. In particular, the mass

spectra displayed the expected molecular ion peaks for M(271a + H) at 297 and for

M(271b + H) at 42 1.

The 'H NMR spectra for each of the unsymmetric 2,2'-bipyridyl ligands 271a (R

= Me) and 271b (R = Ph) is shown below (Figure 2.6.1.). One of the diagnostic features

of the spectra, which revealed the 2-chloro moiety had been substituted with the 2-pyridyl

moiety, was the four additional low field aromatic resonances relative to the 'H NMR

spectra of the starting materials.

- -- I l l I I I ' I ' I

9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 ppm (fl)

1 Figure 2.6.1. H NMR spectra of the unsymmetric 2,2'-bipyridyl ligands 271a,b (R = Me and Ph).

The 13c NMR spectra for each of the unsymmetric 2,2'-bipyridyl ligands 271a (R

= Me) and 271b (R = Ph) is shown below (Figure 2.6.2.). These spectra clearly display

the lack of symmetry in these molecules. For instance, the molecular formula for the

bipyridine ligand 271a (R = Me) is C18H20N202 and the 13c NMR spectrum shows

eighteen signals.

13 Figure 2.6.2. C NMR spectra of the unsymmetric 2,2'-bipyridyl ligands 271a,b (R = Me and

Ph).

2.7. Evaluation of the C2-Symmetric 2,2'-Bipyridyl Ligands (267a-c) in

the Copper(1)-Catalyzed Asymmetric Cyclopropanation Reactions of

Styrene and Diazoesters

With a series of three chiral nonracemic C2-symmetric 2,2'-bipyridyl ligands

267a-c (R = Me, i-Pr and Ph) in hand, the evaluation of these ligands in the copper(1)-

catalyzed asymmetric cyclopropanation (AC) reaction of styrene and diazoesters was

undertaken (Table 2.7.1.). These reactions were performed under a standard set of

reaction conditions that were reviewed earlier in this thesis (Chapter 1, Section 1.9.4.).

Table 2.7.1. Asymmetric Cyclopropanation of Styrene 292

~2~ 293a.b 1.25 mol % Cu(OTf),, 1.3 - 2.6 rnol % ligand L* 267a-c

1.5 rnol % PhNHNH2, CH2CI2, rt, 15 h + *

h\'"

entry L* R L*:Cu ratio product trans:cis yield (%) ee (trans)

55

67

48

47

62

59

53

57

58

No Reaction

The active copper catalyst in these reactions was generated in situ by reduction of

the complex formed between 1.25 mol % of copper(I1) triflate and 1.3 or 2.6 mol % of

the C2-symmetric ligands 267a-c with phenylhydrazine. '29 In all cases, the solutions of

the copper(I1) complexes formed between copper(I1) triflate and 2,2'-bipyridyl ligands

267a-c were light green in colour that turned deep red instantaneously when the

phenylhydrazine was added. This indicated that a reduction process to form the

corresponding copper(1) complexes had occurred.

The AC reactions were carried out at room temperature in dichloromethane and

involved the slow addition (over -3 h) of the ethyl and tert-butyl esters of diazoacetic

acid 293a (R = Et) and 293b (R = t-Bu) to a solution of 2.2 equivalents styrene 292 and

the preformed catalyst. The diastereoselectivity of the cyclopropanation reactions was

determined by analysis of the 'H NMR spectra of the crude reaction products. The yields

listed in the table are the combined yields of the chromatographically separated trans-

and cis-cyclopropanes. The enantiomeric excess of the trans-cyclopropanes was

determined by analytical chiral HPLC (Daicel Chiracel OD column) following reduction

to the corresponding primary alcohols with lithium aluminum hydride. The enantiomeric

excess of the cis-cyclopropanes was not determined due to the fact that it was the minor

reaction product and that it was difficult to separate the enantiomers of this compound on

the analytical Daicel chiral HPLC column.

It was found that both the yields and stereoselectivities of the AC reactions were

highly dependant on which ligand was employed and the ratio of the ligand and

copper(I1) triflate that was employed.

(129) For example, see: Malkov, A. V.; Pemazza, D.; Bell, M.; Bella, M.; Massa, A.; Tepl?, F.; Meghani,

P.; KoEovskjr, P. Synthesis of New Chiral 2,2'-Bipyridyl Ligands and their Application in Copper-

Catalyzed Asymmetric Allylic Oxidation and Cyclopropanation. J. Org. Chem. 2003, 68,4727.

The AC reaction of styrene 292 with ethyl diazoacetate using a 1: 1 ratio of ligand

267a (R = Me) and copper(I1) triflate afforded the cyclopropane 294a in a trans:cis ratio

of 63:37 and in low enantioselectivity (9% ee) (Entry I). Employment of the larger

reaction substrate, tert-butyl diazoacetate, under identical reaction conditions afforded the

cyclopropane 294b in an improved trans:cis ratio of 80:20. However, the

enantioselectivity of the reaction remained low (7% ee) (Entry 2). These results led to

the consideration that the ligand 267a (R = Me) was not completely bound to the

copper(1) salt or that a bis-ligated copper(1) species had formed.'30 To attempt to

improve the stereoselectivities of these initial experiments, the above AC reactions were

repeated using a 2: 1 ratio of ligand 267a (R = Me) to copper(I1) triflate. The reaction

with ethyl diazoacetate afforded the cyclopropane 294a in an improved enantiomeric

excess (24%) as did the reaction with tert-butyl diazoacetate which afforded the

cyclopropane 294b in moderate enantiomeric excess (38%) (Entries 3 and 4,

respectively).

Similar trends were observed in the AC reactions of styrene with the second

ligand 267b (R = i-Pr) that was studied. Using a 1:l ratio of ligand 267b (R = i-Pr) to

copper(I1) triflate, the AC reaction of styrene using ethyl diazoacetate afforded the

cyclopropane 294a in similar enantioselectivity (25% ee) whereas tert-butyl diazoacetate

afforded cyclopropane 294b in slighly higher enantioselectivity (44% ee) (Entries 5 and

6, respectively). The use of a 2:l ratio of ligand 267b (R = i-Pr) to copper(I1) triflate in

the AC reaction of styrene with ethyl diazoacetate improved the enantioselectivity of the

(130) Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A. Semicorrin Metal Complexes as

Enantioselective Catalysts. Helv. Chim. Acta 1988, 71, 1541.

reaction (34% ee) (Entry 7). However, in the case of tert-butyl diazoacetate the

enantiomeric excess remained essentially the same (42%) (Entry 8).

Particularly interesting results were obtained with ligand 267c (R = Ph) in this AC

reaction. Using a 1: 1 ratio of ligand 267c (R = Ph) and copper(I1) triflate in the reaction

of styrene 292 with ethyl diazoacetate 293a, the cyclopropane 294a was isolated in

racemic form (0% ee) (Entry 9). This was very surprising since it was expected that the

ligand 267c (R = Ph) would be the most efficient chiral director of the series because of

the size of the chiral cyclic acetal moiety (R = Ph). Remarkably, when the AC reaction

of styrene with ethyl diazoacetate was repeated with a 2:l ratio of ligand 267c (R = Ph)

and copper(I1) triflate, the cyclopropane product was not formed (Entry 10).

The absolute stereochemistry of the major trans-cyclopropanation products

294a,b when ligand 267a (R = Me) was employed was determined to be (1R,2R) by

comparison of the optical rotation with a literature value.131 As would be expected, the

pseudo-enantiomeric ligand 267b (R = i-Pr) afforded the enantiomeric cyclopropanation

products (1S,2S)-294a,b. These stereochemical outcome of these reactions can be

rationalized in terms of the minimization of steric interactions between the reacting

species and the copper(1) complex of the 2,2'-bipyridyl ligands 267a (R = Me) and 267b

(R = i-Pr). A schematic representation that depicts the proposed low and high energy

modes for the reaction of styrene 292 with the copper-carbene intermediate 295 [with

ligand 267a (R = Me)] that would afford the four possible isomeric cyclopropane reaction

products is shown below (Figure 2.7.1.). The lower energy reaction modes can be

(131) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Highly Enantioselective Cyclopropanation with Co(I1)-

Salen Complexes: Control of cis- and trans-Selectivity by Rational Ligand Design. Adv. Synth. Catal.

2001, 343, 79.

attributed to the minimization of the steric interactions between the chiral acetal

substituents (R) and the styrene 292. Also to note in the figure, attack along reaction

pathway (a) would lead to the major trans-cyclopropane 294 reaction product while

attack along reaction pathway (b) would lead to the minor cis-cyclopropane 294 reaction

product.

Lower Energy Mode

I Higher Energy Mode

(1 R,2R)-trans294 (1 S,2R)-cis-294 (1 S,2S)-trans294 (1 R,2S)-cis-294

[Major-path (a)] [Minor-path (b)] [Major-path (a)] [Minor-path (b)]

Figure 2.7.1. Rationalization of the stereochemical outcome of the AC reactions based on the

minimization of steric interactions between the catalyst and the reacting species.

It was decided to undertake a crystallographic study to probe the structure of the

active catalyst in these AC reactions. The ligand 267c (R = Ph) was selected as

particularly interesting results had been obtained in this case.

Due to the air and moisture sensitivity of copper(1) triflate complexes it was

decided to prepare the corresponding copper(1) chloride complex of the ligand 267c (R =

Ph). Coordination of equimolar amounts of the ligand 267c (R = Ph) and anhydrous

copper(1) chloride in a mixture of ethanol and dichloromethane (1 : 1) at room temperature

for 4 h did not afford the expected mono-ligated CuCl(267c) complex but afforded the

bis-ligated C ~ ( 2 6 7 c ) ~ C u C l ~ complex in quantitative yield. The initial structural

assignment of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex was based on the mass spectrum which

displayed a molecular ion peak that indicated two bipyridine ligands were bound to the

copper centre [I431 (M - CuC12)]. Bright red X-ray quality crystals were then obtained

by recrystallization of the complex upon the slow evaporation of a solution of the

complex Cu(267c)yCuCl2 in ether and dichloromethane (1 : 1). Analysis of the X-ray data

revealed that two 2,2'-bipyridyl ligands 267c (R = Ph) were coordinated to the copper(1)

centre in a tetrahedral geometry. In addition, the chloride counter ion had been displaced

from the coordination sphere of the complex and had combined with the remaining

copper(1) chloride to form a copper(1) dichloride counterion (CuC12-).* An ORTEP

representation of this complex is shown below (Figure 2.7.2.). Around the copper(1)

centre, the following bond angles were observed: N1-Cul-N2 = 82.2" and N2-Cul-Nl* =

13 1.2". The N 1 -Cu 1 bond length was 2.057 A and the N2-Cu 1 bond length was 2.052 A.

Complete tabulated data of bond angles and bond lengths from the X-ray structure

determination of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex are provided in the experimental section

of this thesis.

(*) X-ray crystal structure analysis of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex was performed by Mr. Neil D. Draper

at Simon Fraser University.

Figure 2.7.2. ORTEP representation of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex.'

To rationalize the results from the AC reactions of styrene 292, and particularly

the dependence of the enantioselectivity on the ratio of ligand to copper used in the

reaction, i t is proposed that the ligands 267a-c have a propensity to form his-ligated

copper(1) complexes in solution and thus an equilibrium is established between free

(*) The thermal ellipsoids are drawn at a 25% probability and the hydrogen atoms have been removed for

clarity

copper(1) triflate 296, mono-ligated copper(1) triflate complexes 297, and bis-ligated

copper(1) triflate complexes 298 (Figure 2.7.3.).

CuOTf

296 (active catalyst) 297 (active catalyst)

-

298 (inactive catalyst)

a CuOTf

2

Figure 2.7.3. The proposed equilibrium established in solution of copper(1) triflate and the 2,2'-

bipyridyl ligands 267a-c (R = Me, i-Pr and Ph).

The bis-ligated complexes are presumably inactive cyclopropanation catalysts

since all possible coordination sites on the copper centre are occupied. However, the free

copper(1) triflate 296, and the mono-ligated copper(1) triflate complexes 297 would be

active catalysts and thus the enantioselectivity observed in the AC reactions was a result

of the relative rates of catalysis by these two species. It is possible that the mono-ligated

copper(1) triflate complexes 297 could be very effective chiral directors in the AC

reactions but the free copper(1) triflate in solution had diminished the enantioselectivity

observed in these reactions.

In the case of ligand 267c (R = Ph), the bis-ligated complex appears to be the

major complex in solution. The apparent kinetic and thermodynamic stability of this

particular complex could be due to favorable n-n interactions or that the two ligands are

sterically interlocked once positioned around the copper(1) centre (see, Figure 2.7.2.).

Thus, when a 1:l ratio of ligand 267c to copper was employed in the AC reaction, the

two species in solution were catalytically active free copper(1) triflate and the

catalytically inactive bis-ligated complex Cu(OTo(267~)~ and so the cyclopropane

product was isolated in racemic form. Moreover, when the AC reaction was performed

with a 2: 1 ratio of ligand 267c (R = Ph) and copper, the copper was entirely sequestered

as the bis-ligated complex Cu(OTf)(267~)~ and the cyclopropanation reaction was shut

down completely.

2.8. Evaluation of the Unsymmetric 2,2'-Bipyridyl Ligands [271a,b (R =

Me and Ph)] in Copper@)-Catalyzed Asymmetric Cyclopropanation

Reactions of Styrene and Ethyl Diazoacetate

The unsymmetric 2,2'-bipyridyl ligands 271a,b (R = Me and Ph) were also

evaluated in the AC reaction of styrene 292 (Scheme 2.8.1.). The AC reaction of styrene

292 with ethyl diazoacetate 293a using a 1 : 1 ratio of ligands 271a,b (R = Me and Ph) to

copper(I1) triflate afforded the cyclopropane 294a in good yields (74 and 75%,

respectively). However, these reactions proceeded with very low enantioselectivity in

each instance (2 and 3% ee, respectively). The low enantioselectivities obtained with the

unsymmetric ligands is presumably due to the lack of sufficient steric bulk on one side of

the chiral ligands.

Scheme 2.8.1. Asymmetric Cyclopropanation Reactions using the Unsymmetric 2,2'-Bipyridyl

Ligands 271a,b (R = Me and Ph)

1.25 mol % Cu(OTfI2, 1.25 mol % ligand 271a,c,

1.5 mol % PhNHNH,, CH2C12, rt, 15 h

~ h * L-

The compound used in this study was the enantiomer to that shown in the reaction scheme.

117

2.9. Optical Rotary Dispersion Spectrum of the C ~ ( 2 6 7 c ) ~ C u C l ~

Complex

In the process of undertaking the full spectroscopic characterization of the

C ~ ( 2 6 7 c ) ~ C u C l ~ complex, it was observed that this compound possessed a particularly

large optical rotation ([a] - 1300 [c 0.003, chloroform]). Pfaltz and co-workers have

reported a similarly large optical rotation ([a] i:, - 1574 [c 0.01, ethanol]) for a bis-

ligated copper(I1) semicorrin complex.131 This result led us to record the optical rotary

dispersion spectrum of the complex (Figure 2.9.1.). The spectrum was recorded at a

concentration of 3.0 mg C ~ ( 2 6 7 c ) ~ C u C l ~ complex in 100 mL of chloroform (1.9 x 10'~

M) and across a wavelength range of 200 nm to 800 nm. The maximum positive specific

rotation was + 1.1 x lo4 at a wavelength of 304 nm. The maximum negative specific

rotation was - 1.3 x lo4 at a wavelength of 329 nm (the corresponding circular dichroism

spectrum is provided in the appendices of this thesis, see: Section 9.1.). To put these

values in context, the classic hydrocarbon helicenes have extraordinarily high specific

rotation values ([a] :) that range from 3640 " for [6]-helicene to 9620 " for [13]-

helicene. 132

(132) For a review on the synthesis of helicenes and their physical properties, see: Hopf, H. In Classics in

Hydrocarbon Chemistry; Wiley-VCH: Weinheim, 2000, pp 321-368.

Optical Rotary Dispersion Spectrum

301 nm, +1.1 x loJ A

rrzl

589 nm, -1.5 x 10'

329 nm, -1.3 r I&'

ZOO 300 400 500 600 700 800

Wavelength (nm)

Figure 2.9.1. The optical rotary dispersion spectrum of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex.

A UV spectrum of the Cu(267c)2CuC12 complex was also recorded on the same

sample as that used to obtain the ORD spectrum. Strong UV absorbances at 287 nm (E =

3.8 x lo4 M" cm"), 309 (E = 3.9 x lo4 M" cm") and 472 nm (E = 6.2 x lo3 M-' cm-')

were observed. The absorbance at 472 nm is in the blue-visible region of the

electromagnetic spectrum which accounts for the red colour of the C u ( 2 6 7 ~ ) ~ C u C l ~

complex.

2.10. Conclusions

The efficient and modular synthesis of a series of three chiral nonracemic C2-

symmetric 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr and Ph) and two unsymmetric

2,2'-bipyridyl ligands 271a,b (R = Me and Ph) was developed. These novel ligands were

prepared in two steps from 2-chloro-4-methyl-6,7-dihydro-5H-[l]pyridine-7-one 269 and

a series of chiral C2-symmetric 1,2-diols 270a-c (R = Me, i-Pr and Ph). This

demonstrated the versatility of the design concept that underlies this research program in

asymmetric synthesis.

The C2-symmetric 2,2'-bipyridyl ligands 267a-c and the corresponding

unsymmetric 2,2'-bipyridyl ligands 271a,b were evaluated in the copper(1)-catalyzed

asymmetric cyclopropanation reactions of styrene 292 and diazoesters 293a-c. The

reaction conditions involved the formation of the asymmetric catalyst by reduction of the

complex formed between 1.25 mol % of copper(I1) triflate and 1.3 or 2.6 mol % of the

C2-symmetric ligands 267a-c or the unsymmetric ligands 271a,b with phenylhydrazine in

dichloromethane. Following catalyst formation, styrene 292 was added to the reaction

mixture followed by the slow addition of the diazoester 293a,b over the course of 4 h.

The best result was obtained in the asymmetric cyclopropanation reaction of styrene 292

and tert-butyl diazoacetate 26713 when the ligand 271b (R = i-Pr) was employed. This

afforded the reaction product 294 in good diastereoselectivity (83: 17) and in moderate

enantioselectivity (44% ee) (Scheme 2.10.1 .).

Scheme 2.1 0.1. Asymmetric Cyclopropanation Reaction of Styrene employing the C2-Symmetric

2,2'-Bipyridine Ligand 267b (R = i-Pr) * 0

j-pr\\ ,i(" i-Pi i-Pr

1.3 mol % 1.25 mol % Cu(OTQ2,

1.50 mol % PhNHNH2, CH2CI2, rt, 15 h * Ph""

59%

Lo2t-Bu

294 (44% ee)

In the course of these investigations it was observed that the stereoselectivities as

well as the yields of the asymmetric cyclopropanation reactions were heavily dependant

upon the ratio of the ligand 267a-c and copper(I1) triflate employed. The X-ray structure

determination of the complex formed between the C2-symmetric 2,2'-bipyridyl ligand

267c (R = Ph) and copper(1) chloride showed that two bipyridyl ligands had coordinated

to a copper(1) ion. This information, along with the results from the AC reactions, led to

the conclusion that the 2,2'-bipyridyl ligands 267a-c had the propensity to form

catalytically inactive bis-ligated copper(1) species in solution that were in equilibrium

with a catalytically active free copper(1) species and a mono-ligated copper(1) species. It

was also inferred that the mono-ligated copper(1) species could possibly be very selective

in the AC reactions and that the observed enantioselectivities were significantly eroded

by the free copper(1) species in solution. For this reason, future studies with these ligands

will involve their application in asymmetric reactions which are catalyzed by transition

metals other than copper.

In the process of characterizing the C ~ ( 2 6 7 c ) ~ C u C l ~ complex it was observed that

it had a very large specific optical rotation. An optical rotary dispersion spectrum was

recorded at a high dilution so that it was in the linear range of the instrument (1.9 x

M). The maximum positive optical rotation was + 1.1 x 1 o4 at a wavelength of 304 nm.

The maximum negative optical rotation was -1.3 x lo4 at a wavelength of 329 nm. These

are exceptionally high values and a future study has been considered that will involve the

detection of trace quantities of copper salts and other transition metal salts in solution via

optical rotation measurements (optical-sensing).


SYNTHESIS AND EVALUATION OF NEW CHIRAL NONRA CEMC PYRIDINE N-OXIDES AND BIPYRIDINE

N, N '-DIOXIDES

3.1. Introduction

In this chapter, the syntheses of a chiral nonracemic pyridine N-oxide and a

related chiral nonracemic C2-symmetric 2,2'-bipyridyl N,N'-dioxide are described. The

evaluation of these two chiral N-oxides in the catalytic desymmeterization reaction of cis-

stilbene oxide with silicon tetrachloride is also described.

We envisioned that the chiral nonracemic pyridine N-oxide 299 could be prepared

by simple oxidation of the corresponding pyridine 300. This pyridine 300 could be

prepared by the reduction of the chiral nonracemic 2-chloroacetal 268c (Figure 3.1.1 .).

The 2-chloroacetal268c had previously been used to synthesize the 2,2'-bipyridyl ligands

267a-c (see, Chapter 2).

Me\ Me\ Me\ po 0 O -

C I P h Pt i

p 0

4Ph Pt i

p c 1 0

4Ph Pti

299 300 268c

Figure 3.1 . l . Retrosynthetic analysis of the chiral pyridine N-oxide 299.

In a similar fashion, the C2-symmetric 2,2'-bipyridyl N&'-dioxide 301 could be

prepared by direct oxidation of the corresponding C2-symmetric 2,2'-bipyridyl ligand

267c (Figure 3.1.2.).

Pt?

p 0

MPh Pt?

301 267c

Figure 3.1.2. Retrosynthetic analysis of the chiral nonracemic C2-symmetric 2,2'-bipyridyl N,N'-

dioxide 301.

3.2. Synthesis of the Chiral Nonracemic Pyridine N-Oxide (299)

The chiral nonracemic pyridine 300 was prepared by reduction of the 2-

chloropyridine 268c (Scheme 3.2.1.). This reaction involved heating the 2-

chloropyridine 268 with borane dimethylamine complex in the presence of a catalytic

amount of dibromobis(triphenylphosphine)nickel(II) and potassium carbonate in

acetonitrile at 50 "C which afforded the pyridine 300 in good yield (87%).'33 The

pyridine 300 was then converted to the pyridine N-oxide 299 in excellent yield (93%)

upon oxidation with m-chloroperoxybenzoic acid in dichloromethane at room

temperature.

(133) Lipshutz, B. H.; Tomioka, T.; Pfeiffer, S. S. Mild and Selective Reductions of Aryl Halides

Catalyzed by Low-Valent Nickel Complexes. Tetrahedron Lett. 2001,42,7737.

Scheme 3.2.1. Synthesis of the Chiral Nonracemic Pyridine N-Oxide 299

Reagents and Conditions: (a) NiBr2(PPh3)2, BH3-(Me)2NH, MeCN, 50 OC, 12 h, 87%; (b) m-

CPBA, CH2CI2, room temperature, 24 h, 93%.

The structure of the pyridine N-oxide 299 was confirmed on the basis of

spectroscopic evidence. The mass spectrum was not particularly useful because the

compound fragmented and evidence of the N-oxide moiety was lost. However, elemental

analysis confirmed the molecular formula C23H21N03. In addition, the infrared spectrum

displayed a characteristic pyridine N-oxide stretch at 1258 ~ r n - ' . ' ~ ~ The 'H NMR

spectrum of the pyridine N-oxide 299 is shown below (Figure 3.2.1 .).

1 Figure 3.2.1. H NMR spectrum of the chiral pyridine N-oxide 299.

(134) Silverstein, R. M.; Webster, F. X. Infrared Spectrometry. In Spectrometric Identification of Organic

Compounds, 6thed.; John Wiley & Sons, Inc. New York, 1998; Chapter 3.


The chiral 2,2'-bipyridyl N,N-dioxide 301 was prepared from the corresponding

2,2'-bipyridyl ligand 267c on oxidation with three equivalents of m-chloroperoxybenzoic

acid in dichloromethane at room temperature (Scheme 3.3.1 .).

Scheme 3.3.1. Preparation of the Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl N,N'-Dioxide

301

& m-chloroperoxybenzoic acid (3 equiv), CH2CI2, room temperature, 24 h

86%

Ph

267c 301

The structure of the bipyridine N,N'-dioxide 301 was again confirmed on the

basis of full spectroscopic evidence. In particular, the mass spectrum displayed a

molecular ion peak for M(301 + H) at 717 which indicated both pyridine nitrogen atoms

had been oxidized. The 'H NMR spectrum displayed broadened peaks which suggested

that the barrier to rotation about the biaryl bond was relatively high.

3.4. Evaluation of the Chiral Nonracemic Pyridine N-Oxide (299) and

the C2-Symmetric 2,2'-Bipyridyl N&'-Dioxide (301) in a Catalytic

Desymmeterization Reaction of cis-Stilbene Oxide

The chiral nonracemic pyridine N-oxide 299 and the C2-symmetric 2,2'-bipyridyl

N,W-dioxide 301 were evaluated as chiral directors in the catalytic desymmeterization

reaction of a meso compound, cis-stilbene oxide 302, with silicon tetrachloride (Figure

3.4.1.) . '~~ The reaction conditions involved the addition of silicon tetrachloride to a

solution of 10 mol % of the chiral pyridine N-oxide (299 or 301), N,N-

diisopropylethylamine and cis-stilbeneoxide 302 in dichloromethane at -78 "C. The

chiral pyridine N-oxide 299 was catalytically active and afforded the desired chiral

chlorohydrin 303 in excellent yield (95%) and moderate enantiomeric excess (20%).

However, in the case of the 2,2'-bipyridyl N,N'-dioxide 301, no reaction occurred and

only starting material was recovered after 24 h. The catalytic inactivity of the 2,2'-

bipyridyl N,N'-dioxide 301 can be attributed to the high degree of steric hindrance around

the complexation pocket of the catalyst. Due to the lack of reactivity and the low

enantioselectivity, these chiral N-oxides were not evaluated in asymmetric aldol reactions

(see, section 1.1 1.) and it was decided to pursue the synthesis and evaluation of other

chiral ligands.

(135) (a) Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, H. Enantioselective Ring-Opening of meso-

Epoxides with Tetrachlorosilane Catalyzed by Chiral Bipyridine N,N'-Dioxide Derivatives. Tetrahedron

Lett. 2002, 43, 8827. (b) Garrett, C. E.; Fu, G. C. n-Bound Phosphorus Heterocycles as Catalysts: Ring-

Opening of Expoxides with TMSCl in the Presence of a Phosphaferrocene. J. Org. Chem. 1997, 62, 4534.

(c) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. Enantioselective Ring-Opening of

Epoxides with Silicon Tetrachloride in the Presence of a Chiral Lewis Base. J. Org. Chem. 1998, 63, 2428.

Scheme 3.4.1. The Desymmeterization Reactions of cis-Stilbene oxide 302

10 mol % pyridine N-oxide 299 or 301 cl SiCI4, (i-PrhNEt, CH2CI2, -78 "C, 24 h p h Y H

Ph * 0-95% Ph

meso-302 303 (20% ee)

3.5. Conclusions

The chiral nonracemic pyridine N-oxide 299 and the C2-symmetric 2,2'-bipyridyl

N,N'-dioxide 301 were prepared by direct oxidation of the corresponding chiral pyridine

300 and C2-symmetric 2,2'-bipyridyl 267c, respectively. These N-oxides were evaluated

as chiral catalysts in the asymmetric desymmeterization reaction of cis-stilbene oxide

with silicon tetrachloride. The pyridine N-oxide 299 was an active catalyst in this

reaction and afforded the reaction product in excellent yield but in low enantioselectivity.

The C2-symmetric 2,2'-bipyridyl NjV-dioxide 301 was found to be catalytically inactive

in this reaction.


SYNTHESIS AND EVALUATION OF A SERIES OF NEW CHIRAL NONRA CElMlC PYRIDYLPHOSPHINE

LIGANDS

4.1. Introduction

In this chapter, the efficient and modular synthesis of a new class of chiral

nonracemic pyridylphosphine ligands (P,N-ligands) is described.* The syntheses of these

ligands represents an extension of the general design concept described in Chapter 1.

Their syntheses were pursued in order to further demonstrate the modular nature of this

approach as well as to identify a highly effective chiral director. The evaluation of these

Pa-ligands in palladium-catalyzed asymmetric Heck reactions, in palladium-catalyzed

asymmetric allylic substitution reactions as well as in the iridium(1)-catalyzed

asymmetric hydrogenation reactions is also presented.

The chiral nonracemic Pa-ligands 304a-c (R = Me, i-Pr and Ph) could in

principle be synthesized from the corresponding chiral chloroacetals 268a-c, the same

precursors that were used in the synthesis of the chiral2,2'-bipyridyl ligands 267a-c (see,

Chapter 2). We envisioned that a Suzuki coupling reaction of the chloroacetals 268a-c

with ovtho-fluorophenylboronic acid 306 would afford the biaryl fluorides 305a-c that on

displacement of fluoride ion with the anion of diphenylphosphine would afford the

desired P,N-ligands 304a-c (Figure 4.1.1 .).

--

(*) Part of the research described in this chapter has been published, see: Lyle, M. P. A.; Narine, A. A.;

Wilson, P. D. A New Class of Chiral P,N-Ligands and their Application in Palladium-Catalyzed

Asymmetric Allylic Substitution Reactions. J. Org. Chem. 2004, 69, 5060.

Me.

304a-c (R = Me, i-Pr and Ph) 305a-c 268a-c 306

Figure 4.1.1. Retrosynthetic analysis of the chiral P,N-Ligands 304a-c (R = Me, i-Pr and Ph).

4.2. Synthesis of the Chiral Nonracemic PJV-Ligands [304a-c (R = Me,

i-Pr and Ph)] from the Chiral Acetals (268a-c)

The chiral nonracemic chloroacetals 268a-c (R = Me, i-Pr and Ph) were each

subjected to a Suzuki coupling reaction with o-fluorophenylboronic acid 306 (Scheme

4.2 .1 . ) . '~~ It was again found that the 2-chloropyridine moiety of these acetals reacted

exceedingly slowly with this boronic acid under standard Suzuki reaction conditions

which involved heating a mixture of the chloroacetals 268a-c, the boronic acid 306 and

potassium carbonate in toluene in the presence of 10 mol %

tetrakis(triphenylphosphine)palladium(O). However, the reactions proceeded smoothly

when the reaction conditions reported by Fu and co-workers were employed and afforded

the desired reaction products, the aromatic fluorides 305a-c (R = Me, i-Pr and Ph), in

good yield (81-93%).'~~ These reaction conditions involved heating a mixture of the

acetals 268a-c (R = Me, i-Pr and Ph), the boronic acid 306 and anhydrous cesium

(136) For a review on the Suzuki reaction, see: Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross

Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995,95,2457.

(137) Littke, A. F.; Dai, C.; Fu, G. C. Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic

Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions. J. Am. Chem. Soc. 2000, 122,

4020.

carbonate in tetrahydrofuran at reflux in the presence of catalytic amounts of

tris(dibenzylideneacetone)dipalladium(0) (5 mol %) and tri-t-butylphosphine (1 0 mol %).

Scheme 4.2.1. Synthesis of the

a - Me. i-Pr and

b -

268a-c (R = ~ e ' , i-Pr and Ph) 305a-c (R = ~ e * , i-Pr and Ph) 304a-c (R = ~ e * , i-Pr and Ph)

Reagents and conditions: (a) o-fluorophenylboronic acid 306, 5 mol% of Pd2dba3, 10 molOh of

P(~-Bu)~, Cs2C03, THF, reflux, 16 h, 93% (305a), 81% (305b), 88% (305~); (b) HPPh,, KOt-Bu,

* 18-crown-6, THF, room temperature, 24 h, 72% (304a), 66% (304b), 63% (304~). The

compound used in this study was the enantiomer of that shown in the reaction scheme.

The products of the Suzuki reactions were then converted efficiently to the

desired target compounds, the chiral nonracemic P,N-ligands 304a-c (R = Me, i-Pr and

Ph), on reaction of the potassium salt of diphenylphosphine in the presence of 18-crown-

6 in tetrahydrofuran at room temperature for 24 hours.'38 The potassium salt of

diphenylphosphine was prepared by treatment of a colourless solution of

diphenylphosphine in tetrahydrofuran with potassium tert-butoxide. This afforded a

bright red solution of the anion that faded to yellow over the course of the reaction, once

the aromatic fluorides 305a-c were added.

The mass spectra for each of the P,N-ligands 304a-c (R = Me, i-Pr and Ph)

displayed the expected molecular ion peaks for M(304a + H) at 480, for M(304b + H) at

536 and for M(304c + H) at 604. The 'H NMR spectra of the Pa-ligands 304a-c (R =

(138) Kiindig, E. P.; Meier, P. Synthesis of New Chiral Bidentate (Phosphinopheny1)benzooxazine P,N-

Ligands. Helv. Chim. Acta 1999,82, 1360.

Me, i-Pr and Ph) are shown below (Figure 4.2.1 .). These sharp, well-resolved spectra

suggested that there was free rotation about the biaryl bond in each of the Pa-ligands

304a-c and thus there were no atropisomeric forms of these molecules. In addition, the

13 C NMR spectra of these unsymmetrical molecules contained the appropriate number of

signals.

Figure 4.2.1. 'H NMR spectra of the P,N-ligands 304a-c (R = Me, i-Pr and Ph).

4.3. X-Ray Crystallographic Analysis of the Chiral PJV-Ligand [304c

(R = Ph)]

In the course of these investigations, a sample of the chiral PJV-ligand 304c (R =

Ph) was provided to Mr. Neil D. Draper of Professor Daniel B. Leznoff s research group

at Simon Fraser University who was interested in synthesizing chiral coordination

polymers of this P,N-ligand and mercury(I1) cyanide.'39 In one experiment, equimolar

amounts of the PJV-ligand 304c (R = Ph) and mercury(I1) cyanide were dissolved in a

mixture of ethanol and dichloromethane (1: 1). Colourless crystals that were suitable for

X-ray crystallography were obtained on slow evaporation of the solvent mixture. When

the crystals were collected and analyzed by X-ray crystallography it was revealed that the

crystals were not a coordination polymer but were crystals of the non-complexed P,N-

ligand 304c (R = Ph).

An ORTEP representation of the crystal structure of the ligand 304c is shown

below (Figure 4.3.1.). Notably, in the solid state, the chiral P,N-ligand 304c (R = Ph)

showed a preference for one atropisomeric state in which the biaryl bond was rotated

such that the phosphorus atom (PI) was oriented on the same side of the molecule as the

oxygen atom (01). A complete list of tabulated bond angles and bond lengths from the

X-ray structure determination of the P,N-ligand 304c (R = Ph) is provided in the

experimental section of this thesis.

(139) (a) Draper, N. D.; Batchelor, R. J.; Leznoff, D. B. Tuning the Structures of Mercury Cyanide-Based

Coordination Polymers with Transition Metal Cations. Crystal Growth and Design 2004, 4, 62 1. (b)

Haftbaradaran, F.; Draper, N. D.; Leznoff, D. B.; Williams, V. E. A Strained Silver(1) Coordination

Polymer of 1,4-Diazatriphenylene. J. Chem. Soc., Dalton Trans. 2003, 2105. (c) Draper, N. D.; Batchelor,

R. J.; Leznoff, D. B. Using HgX2 Units (X = CN, C1) to Increase Structural and Magnetic Dimensionality

in Conjunction with (2,2'-Bipyridyl)copper(II) Building Blocks. Polyhedron 2003,22, 1735.

Figure 4.3.1. ORTEP representation of the chiral P,N-ligand 304c (R = Ph).'

4.4. Evaluation of the P,N-Ligands (304a-c) in Palladium-Catalyzed

Asymmetric Heck Reactions of 2,3-Dihydrofuran (307)

With a series of three chiral nonracemic P,N-ligands 304a-c (R = Me, i-Pr and Ph)

in hand, the evaluation of the ligands in the palladium(0)-catalyzed asymmetric Heck

reactions of phenyl triflate 308 with 2,3-dihydrofuran 307 were undertaken (Table 4.4.1 .).

These asymmetric carbon-carbon bond forming reactions were performed under standard

reaction conditions that were reviewed earlier in this thesis (see, Chapter 1 - Section

(*) The thermal ellipsoids are drawn at the 25% probability level for clarity.

Table 4.4.1. Palladium-Catalyzed Asymmetric Heck Reactions

307 1.5 mol % Pd2dba3 3 mot % P,N-ligand 304a-c (R = Me, i-Pr and Ph)

(i-Pr),NEt, benzene, 70 "C, 3 days +

0 - 59%

PhOTf 308

entry ligand yield (%) %ee

1 304a (R = Me) 2 304b (R = i-Pr) 3 304c (R = Ph)

The catalysts were formed in situ on reaction of 1.5 mol % of

trisbenzylideneacetonedipalladium(0) with 3 mol % of the chiral P,N-ligand 304a-c (R =

Me, i-Pr and Ph) in anhydrous and degassed benzene which afforded deep purple

solutions. Following the formation of the catalysts, 2,3-dihydrofuran 307, phenyl triflate

308 and Nfl-diisopropylethylamine were added to the reaction mixture which was then

heated at 70 OC for 3 days.

In the case of the P,N-ligand 304a (R = Me), the system proved to be catalytically

active and afforded the desired Heck reaction product 309 in moderate yield (59%) but in

low enantiomeric excess (22%) (entry 1). The absolute stereochemistry of the reaction

product 309 was assigned as (S) based on comparison of the optical rotation to a literature

value.140 The palladium(0)-catalysts derived from the P,N-ligands 304b,c (R = i-Pr and

Ph) did not catalyze the reaction under these conditions and none of the desired reaction

product was isolated. The lack of reactivity of the P,N-ligands 304b,c (R = i-Pr and Ph)

(140) Gilbertson, S. R.; Xie, D.; Fu, Z. Proline-Based P,N Ligands in Asymmetric Allylation and the Heck

Reaction. J. Org. Chem. 2001, 66, 7240.

was attributed to steric hindrance around the complexation pocket of the palladium(0)

centre.

In view of the low enantiomeric excess (22%) recorded with ligand 304a (R =

Me) and the catalytic inactivity of the other systems, it was concluded that the chiral

nonracemic P,N-ligands 304a-c were not well suited to application in asymmetric Heck

reactions and so it was decided to evaluate these ligands in other asymmetric reactions.

4.5. Evaluation of the PJV-Ligands (304a-c) in Palladium-Catalyzed

Asymmetric Allylic Substitution Reactions

The evaluation of the series of three chiral P,N-ligands 304a-c (R = Me, i-Pr and

Ph) in the palladium(I1)-catalyzed asymmetric allylic substitution (AAS) reaction of

racemic 3-acetoxy- l,3-diphenyl- 1 -propene RS-310 with dimethyl malonate 311 was

undertaken (Table 4.5.1 .). These reactions were again performed under standard reaction

conditions that were reviewed earlier in this thesis (Chapter 1, Section 1.12.4.).

Table 4.5.1. Palladium-Catalyzed Asymmetric Allylic Substitution Reactions

Me02C,,C02Me 31 1 2.5 rnol % [ P ~ C I ( ~ ~ - C ~ H ~ ) ] ~ ,

(3 equiv) + 6.25 mol % P,N-ligand 304a-c,

base, CH2CI2, 2-24 h M e o 2 C ~ Co2Me

OAc + Ph 4 P h 312 dPh RS-310 58-90%

Ph

-- - -- - -- - -- -- --

entry ligand base temp. ("C) yield (%) ee (%) conf.

BSNKOAc (cat.)

K2CO3, 18-crown-6

cs2co3

BSNKOAc (cat.)

K2CO3, 18-crown-6

cs2co3

BSNKOAc (cat.)

K2CO3, 18-crown-6

cs2co3

cs2co3

Cs2C03

cs2co3

The active chiral palladium(I1)-catalysts were generated by the reaction of 6.25

mol % of the chiral P,N-ligand 304a-c (R = Me, i-Pr and Ph) with 2.5 rnol % of

allylpalladium chloride dimer in anhydrous dichloromethane at room temperature for 30

min which afforded pale yellow solutions. On subsequent addition of racemic 3-acetoxy-

1,3-diphenyl-1-propene RS-310 (1 equiv) and dimethyl malonate 311 (3 equiv) a range of

bases and associated reagents were then added. The bases and associated reagents used

in these reactions were as follows: (I) NO-bis(trimethylsily1)acetamide (BSA, 3 equiv)

and a catalytic amount of potassium acetate; (2) anhydrous potassium carbonate (3 equiv)

and 18-crown-6 (3 equiv); and (3) anhydrous cesium carbonate (3 equiv). These bases

and associated reagents were chosen so that we could evaluate the effect of the

counterion of the anion of dimethyl malonate on the stereoselectivity of the reaction.14'

The nucleophilic species generated from each of these sets of reagents are shown below

(Figure 4.5.1.).

313 31 4 31 5

Figure 4.5.1. The nucleophilic species associated with each of the reagents used in the AAS

reactions.

The yields reported in the table are of the analytically pure reaction product that

was isolated by flash chromatography. The enantioselectivity of the reactions were

determined by analytical chiral HPLC (Daicel Chiracel OD column) using hexane:iso-

propanol (97:3) as the eluant with a flow rate of 0.5 mL/minute and UV detection at 245

nm.

In all cases, these catalytic systems proved to be active and afforded the desired

product, 1,3-(diphenylal1yl)malonic acid dimethyl ester 312 in excellent yield (up to

97%). The 'H NMR spectrum of the reaction product 312 clearly showed that the acetate

moiety had been displaced by the anion of dimethyl malonate. In particular, the spectrum

(141) For discussions on the effect of the counter-ion on the enantioselectivity in AAS reactions, see: (a)

Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Mechanistic and Synthetic Studies in Catalytic Allylic Alkylation

with Palladium Complexes of 1-(2-Diphenylphosphino-1-napthy1)isoquinoline. Tetrahedron 1994, 50,

4493. (b) Bovens, M.; Togni, A.; Venanzi, L. M. Asymmetric Allylic Alkylation with Palladium

Coordinated to a New Optically Active Pyrazolylmethane Ligand. J. Organornet. Chem. 1993, 451, C28.

contained two 3H singlets at 3.52 ppm and 3.72 ppm, respectively, which correspond to

the two diastereotopic methyl ester moieties.

It was found that the enantioselectivities of these reactions varied depending on

which P,N-ligand as well as which set of reaction conditions were employed. The use of

the P,N-ligand 304a (R = Me), derived from (2R,3R)-2,3-butanediol 270a, afforded the

product S-312 in good enantiomeric excess (60-65%) (entries 1, 2 and 3) with the three

individual sets of reaction conditions. These results were particularly encouraging when

one considers that these asymmetric reactions were directed by the steric influence of a

methyl group. The use of the pseudo-enantiomeric P,N-ligand 304b (R = i-Pr), derived

from (lS,2S)- 1.2-diisopropyl- 1,2-ethanediol 270b, afforded the enantiomeric product R-

312 in similar enantiomeric excess (43-60%) (entries 4, 5 and 6). It was somewhat

surprising that the use of ligand 304b (R = i-Pr) showed, in general, slightly lower

enantioselectivity (in view of of the presumed greater steric influence of an isopropyl

group relative to a methyl group). The superior result (60% ee) was achieved when

cesium carbonate was used as the base (entry 6). The use of P,N-ligand 304c (R = Ph),

derived from (lS,2S)- 1,2-diphenyl- 1,2-ethanediol 270c, again afforded the product in

moderate enantiomeric excess (58 and 62%) when BSA and a catalytic amount of

potassium acetate or potassium carbonate and 18-crown-6 were employed (enties 7 and

8). However, and to our delight, the product R-312 was formed in high enantiomeric

excess (86%) and in excellent yield (97%) when cesium carbonate was used as the base

in this room temperature reaction (entry 9). On decreasing the temperature to 12 O C a

further enhancement of the enantioselectivity of the reaction was observed (88% ee)

(entry 10). The optimal conditions involved performing the reaction with cesium

carbonate as the base at 0 OC for 4 h. This afforded the product R-312 in good yield

(9 1 %) and in high enantiomeric excess (90%) (entry 1 1). A further decrease in the

reaction temperature to -12 OC did not result in any further improvement in the

enantioselectivity of the reaction (90%) and the yield of the reaction was compromised

(83%) (entry 12).

4.6. Mechanistic Analysis of the Asymmetric Allylic Substitution

Reaction using the Pa-Ligand [304c (R = Ph)]

In order to postulate a plausible mechanism for this highly enantioselective

reaction (90% ee), a 3 1 ~ NMR study of the corresponding cationic r-ally1 palladium

complex was undertaken.

3-Chloro-l,3-diphenyl-l-propene 317 was prepared by the reaction of 1,3-

diphenyl- 1 -propene-3-01 3 16 with concentrated hydrochloric acid at room temperature

followed by purification of the crude reaction product by short path di~ti1lation.l~~ (1,3-

Diphenylallyl)palladium chloride dimer 318 was then prepared according to a literature

procedure described by Bosnich and c o - ~ o r k e r s . ' ~ ~ This involved the reaction of 3-

chloro-l,3-diphenyl-1 -propene 317 with palladium(I1) chloride under an atmosphere of

carbon monoxide and in the presence of lithium chloride (Scheme 4.6.1 .).

(142) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. Asymmetric Synthesis

Catalyzed by Chiral Ferrocenylphosphine-Transition-Metal Complexes. Palladium Catalyzed Asymmetric

Allylic Arnination. J. Am. Chem. Soc. 1989, 1 11, 630 1.

(143) (a) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. Asymmetric Synthesis. Asymmetric Catalytic

Allylation using Palladium Chiral Phosphine Complexes. J. Am. Chem. Soc. 1985, 107, 2033. (b)

Mackenzie, P. B.; Whelan, J.; Bosnich, B. Asymmetric Synthesis. Mechanism of Asymmetric Catalytic

Allylation. J. Am. Chem. Soc. 1985, 107,2046.

Scheme 4.6.1. Preparation of (1,3-Dipheny1)allylpalladium Chloride Dimer

316 31 7 31 8

Reagents and conditions: (a) concentrated HCI, room temperature, 30 min, 65%; (b) PdCI2, LiCI,

H20, EtOH, CO (1 atm), 45 "C for 3 h then room temperature for 24 h, 100%.

The corresponding cationic n-ally1 palladium complex 319 was prepared in

deuterated dichloromethane by the reaction of (1,3-diphenylally1)palladium chloride

dimer 318 and the P,N-ligand 304c (R = Ph) in the presence of silver tetrafluoroborate

which afforded a light yellow solution (Scheme 4.6.2.).144

Scheme 4.6.2. Synthesis of the Cationic IT-Allyl Palladium Complex 319

- g a d 3O4c ( = Ph), AgBF4, CD2C12,

room temperature, 30 min [(v3-1 ,3-diphenylallyl)PdCl]2 t BF4

100%

31 8 L 31 9 A

Examination of the 3 1 ~ NMR spectrum of the cationic n-ally1 palladium complex

319 in deuterated dichloromethane at room temperature indicated the formation of two

isomeric complexes in approximately a 2: 1 ratio (Figure 4.6.1 .).

(144) Gilbertson, S. R.; Lan, P. Kinetic Resolution in Palladium-Catalyzed Asymmetric Allylic Alkylations

by a P,O Ligand System. Org. Lett. 2001,3,2237.

31 Figure 4.6.1. P NMR spectrum of the cationic rr-allyl palladium complex 319.

These isomeric n-ally1 palladium complexes were assigned as the W- and M-

isomers (W- and M-320c), respectively (Figure 4.6.2.).'45 This assignment was made

upon careful inspection of molecular models of the M- and W-isomers of the n-ally1

intermediate. It was observed that the isomer M-320c was more sterically encumbered,

and presumably less stable, than the corresponding isomer W-320c. This would be due to

the close proximity of the 1,3-diphenylallyl moiety and one of the phenyl rings on the

acetal moiety as indicated by the double headed arrow in the figure. It was attempted to

make a definitive assignment of the M- and W-isomers based on 'H NMR data.

However, this was not possible due to the complexity of the spectra. Of note, other

isomeric forms of the n-ally1 complexes are possible. However, the M- and W-isomers

are presumed to be the mechanistically relevant and predominant n-ally1 intermediate^.'^^

(145) For discussions on the assignment of the M- and W-isomers in related catalytic systems, see: (a)

Mancherio, 0. G.; Priego, J.; Ramon, S. C.; Arrayas, R. G.; Liamas, T.; Carretero, C. l-Phosphino-2-

sulfenylferrocenes as Planar Chiral Ligands in Enantioselective Palladium-Catalyzed Allylic Substitutions.

J. Org. Chem. 2003, 68, 3679. (b) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagnt, M.

R. Application of Chiral Mixed Phosphorus/Sulfur Ligands to Palladium-Catalyzed Allylic Substitutions. J.

Am. Chem. Soc. 2000,122,7905.

W-320c (major)

S-312 (minor)

M-320c (minor) \ o Nu

Ph Lph R-312 (major)

Figure 4.6.2. Isomeric rr-allyl intermediates W- and M-320c and stereochemical rationale [Nu =

CH(COMe)2].

Assuming that these intermediates are involved in the reaction of racemic 3-

acetoxy- 1,3 -diphenyl- 1 -propene RS-310 with dimethyl malonate 31 1 in the presence of

the P,N-ligand 304c (R = Ph) and allylpalladium(II) chloride dimer, the reaction pathway

can be described by a Curtin Hammett scheme.'46

The Curtin-Hammett kinetic scheme describes a common situation in organic

chemistry in which a molecule can exist in two interconverting conformational forms,

each of which reacts to give a different reaction product. Recently, a definition of the

Curtin-Hammett principle has been outlined by the International Union of Pure and

Applied Chemistry (IUPAC) and it reads as follows; "Curtin-Hammett Principle: In a

chemical reaction that yields one product from one conformational isomer and a different

product from another conformational isomer (and provided these two isomers are rapidly

(146) Seeman, J. I. Effect of Conformational Change on Reactivity in Organic Chemistry. Evaluations,

Applications, and Extensions of Curtin-Hammett Winstein-Holness Kinetics. Chem. Rev. 1983, 83, 83.

interconvertible relative to the rate of product formation, whereas the products do not

interconvert), the product composition is not solely dependant on the relative proportions

of the conformational isomers in the substrate; it is controlled by the differences in

,, 147 standard Gibbs energies of the respective transition states .

Thus, in this AAS reaction, the interconversion of the W- and M-isomers (W- and

M-320c) can be assumed to be rapid with respect to nucleophilic attack of the anion of

dimethyl malonate (approximately a 2: 1 ratio of r-ally1 intermediates led to a 95:5 ratio

of enantiomeric products).

It would be expected that nucleophilic attack of the anion of dimethyl malonate

on these r-ally1 intermediates W- and M-320c would occur regioselectively trans to the

phosphine moiety because of the strong trans-effect for the phosphorus donor atom

relative to the pyridine nitrogen.94 The trans-effect lengthens the palladium-carbon bond

that is trans to the phosphorus donor atom relative to the bond that is trans to the nitrogen

donor atom. It would also be expected that the nucleophile would attack the exterior

(more open) face of the ally1 moiety (for additional clarification, see: Chapter 1, Figure

1.12.1 .). Thus, to account for the observed absolute stereochemistry of the major reaction

product, (1R)-(1,3-diphenylal1y)malonic acid dimethyl ester R-312, it was concluded that

the z-ally1 intermediate M-320c reacted at a faster rate with the anion of dimethyl

malonate from the angle of attack shown in the figure. In support of these arguments, a

related stereochemical interpretation has recently been reported by Helmchen and Pfaltz

for a related ~ , ~ - l i ~ a n d . ' ~ '

(147) Gold, V. Glossary of Terms used in Physical Organic Chemistry. Pure Appl. Chem. 1979,51, 1725.

(148) (a) Helmchen, G.; Pfaltz, A. Phosphinooxazolines - A New Class of Versatile, Modular P,N-Ligands

for Asymmetric Catalysis. Acc. Chem. Rex 2000, 33, 336. (b) Pfaltz, A.; Drury 111, W. J. Design of Chiral

4.7. X-Ray Crystallographic Analysis of the Palladium(I1) Chloride

Complex of the Pa-Ligand [304a (R = Me)]

To probe the structure of the active catalytic species in these AAS reactions, the

palladium(I1) chloride complex of the P,N-ligand 304a was prepared by heating a

mixture of equimolar amounts of palladium(I1) chloride and the ligand 304a in a mixture

of ethanol and dichloromethane (1:l). Recrystallization of the resultant palladium

complex from ethanol afforded orange X-ray quality crystals.

The X-ray crystallographic analysis of the palladium(I1) chloride P,N-ligand 304a

complex clearly illustrated the orthogonal relationship of the acetal ring and the pyridine

ring that results in the shielding of one of the diastereotopic faces of the complexes of the

chiral P,N-ligands 304a-c (R = Me, i-Pr and Ph) (Figure 4.7.1.).* A distorted square-

planar geometry around the palladium centre was also noted. An interaction between the

acetal oxygen atom (02) and the palladium centre (Pdl) with an interatomic distance of

2.846 A was observed. It is unclear if this interaction occurs in solution and what effect

it may have on the reactivity of the complex. The complex, in the solid-state, is locked in

one atropisomeric form with a torsion angle of 35.8 " around the biaryl bond which is

controlled by the chirality of the cyclic acetal. As expected, the Pd-C1 bond that is trans

to the phosphine moiety is substantially longer than the Pd-Cl bond that is trans to the

pyridine nitrogen (2.377 and 2.299 A, respectively). This clearly reflected the stronger

trans effect of the phosphine moiety and supported the mechanistic assumption that

Ligands for Asymmetric Catalysis. From C2-Symmetric P,P and N,N-Ligands to Sterically and

Electronically Nonsymmetrical P,N-Ligands. Proc. Nut. Acad. Sci. 2004, 101, 5723.

(*) X-ray crystallographic analysis of the PdC12=P,N-ligand 304a complex was performed by Mr. Neil D.

Draper at Simon Fraser University.

nucleophilic addition of the anion of dimethyl malonate to the z-ally1 intermediate

occurred regioselectively trans to the phosphine moiety. Complete tabulated bond

lengths and bond angles from the X-ray structure determination of the palladium(I1)

chloride P,N-ligand 304a complex are listed in the experimental section of this thesis.

Figure 4.7.1. ORTEP representation of the PdC12.P,N-ligand 304a complex.*

4.8. Attempted Application of the Pa-Ligands 304a-c in Iridium-

Catalyzed Asymmetric Hydrogenation Reactions

Iridium(1) complexes with chiral phosphinooxazoline ligands have emerged as

promising asymmetric hydrogenation catalysts. For example, Pfaltz and co-workers have

(*) The thermal ellipsoids are drawn at the 25% probability level for clarity.

recently reported the asymmetric hydrogenation reactions of trisubstituted 1,2-

diarylalkene~. '~~ Using the iridium(1) phosphinooxazoline COD complex 322 with a

tetrakis[2,6-bis(trifluoromethyl)phenyl]borate (TFPB) counterion, high

enantioselectivities (91-98% ee) were achieved with very low catalyst loadings (0.1-0.5

mol %) in dichloromethane at room temperature (Scheme 4.8.1 .).

Scheme 4.8.1. An Asymmetric Hydrogenation Reaction with the Chiral Iridium(1)

Phosphinooxazoline Complex 322

0.1 - 0.5 mol % 322, Hz (50 bar), CH2CI2, room temperature

* 95%

32 1 323 (98% ee)

In order to evaluate the Pfl-ligands 304a-c (R = Me, i-Pr and Ph) in the above

hydrogenation reaction, the corresponding Ir(I)(Pfl-ligand 304a-c)(COD)(TFPB)

complexes 324a-c were prepared. This was achieved by heating the P,N-ligands 304a-c

with iridium cyclooctadiene chloride dimer 325 in dichloromethane at reflux for 1 h. The

reaction mixtures were then treated with NaTFPB and water at room temperature for 15

min. The resultant complexes were purified by crystallization from ethanol upon the

slow addition of water which afforded the Ir(I)(Pfl-ligand 304a-c)(COD)(TFPB)

(149) Lightfoot, A.; Schnider, P.; Pfaltz, A. Enantioselective Hydrogenation of Olefins with Iridium-

Phosphanodihydrooxazole Catalysts. Angew. Chem., Int. Ed. 1998, 37, 2897.

complexes 324a-c as orange crystalline solids which were air stable (Scheme 4.8.2.).150

Satisfactory elemental analyses for each of these compounds was obtained.

Scheme 4.8.2. Synthesis of the Chiral Iridium(1)-Complexes 324a-c

304a-c (R = Me, i-Pr and Ph) 324a-c (R = Me, i-Pr and Ph)

Reagents and conditions: (a) [Ir(COD)C1I2 325, CH2CI2, reflux, 1 h then NaTFPB, H20, room

temperature, 15 min, 91 % (324a), 94% (324b), 90% (324~) .

The Ir(I)(P,N-ligand 304a-c)(COD)(TFPB) complexes 324a-c were first

evaluated in the asymmetric hydrogenation reaction of 1-methoxy-4-[(IT)-2-phenylprop-

1-enyllbenzene 328. This substrate was prepared by a palladium(I1) acetate-catalyzed

reaction of phenylboronic acid 327 and trans-anethole 326 in dimethylfonnamide under

an oxygen atmosphere (balloon pressure) and in the presence of sodium carbonate

(Scheme 4.8.3.).15'

(150) (a) Kainz, S.; Brinkrnann, A.; Leitner, W.; Pfaltz, A. Iridium-Catalyzed Enantioselective

Hydrogenation of Imines in Supercritical Carbon Dioxide. J. Am. Chem. Soc. 1999, 121,6421.

(151) Jung, Y. J.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Oxygen-Promoted Pd(I1) Catalysis for the

Coupling of Organoboron Compounds and Olefins. Org. Lett. 2003,5,223 1.

Scheme 4.8.3. Synthesis of the Asymmetric Hydrogenation Reaction Substrate 328

H3C0 J'y 326 Me

8.0 mol % Pd(OAch, Na2C03, 02, DMF, 50 OC, 3 h

+ 42 %

(H012B\0 327 328

The asymmetric hydrogenation reaction of the alkene 328 was first attempted

with 1 mol % of the Ir(I)(P,N-ligand 304a)(COD)(TFPB) complex 324a in

dichloromethane at room temperature in a high-pressure reaction vessel under an

atmosphere of hydrogen (50 bar). After 24 hours, none of the desired reduction product

was isolated. The reaction conditions were then modified and this reaction was

performed with 5 mol % of the Ir(I)(P,N-ligand 304a)(COD)(TFPB) complex 324a in

dichloromethane at room temperature in a high-pressure reaction vessel under an

atmosphere of hydrogen (100 bar). However, after 24 hours of reaction time, none of the

desired product was isolated.

The reduction of the alkene 328 was also attempted with the other two chiral

Ir(I)(P,N-ligand)(COD)(TFPB) complexes 324b,c under the latter set of conditions.

Again, none of the desired reduction products were isolated.

It was then decided to attempt the hydrogenation of a more reactive alkene in

order to determine if the lack of catalytic activity of the Ir(I)(P,N-ligand)(COD)(TFPB)

complexes 324a-c was substrate dependant. The alkene substrate chosen was methyl a-

acetamidocinnamate 332. This substrate was prepared by heating a mixture of

benzaldehyde 329 and glycine 330 in acetic anhydride to afford the oxazolone 331 in

74% yield.'52 This compound was then heated in methanol at reflux in the presence of

sodium acetate to afford the methyl a-acetamidocinnamate 332 in 75% yield (Scheme

Scheme 4.8.4. Synthesis of Methyl a-acetarnidocinnarnate 332

0 a b

Ph AH + H2NVC02H --+ phyCo2Me N HAc

Reagents and conditions: (a) AQO, NaOAc, reflux, 1 h, 74%. (b) CH30H, NaOAc, reflux, 3.5 h,

75%.

Unfortunately, the attempted asymmetric hydrogenation reaction of the substrate

332 with 5 mol % of the iridium(1) complexes 324a-c in dichloromethane at room

temperature in a high-pressure reaction vessel under an atmosphere of hydrogen (100 bar)

for 24 hours did not afford any of the desired reaction product.

4.9. Conclusions

An efficient and modular synthesis of a series of three chiral nonracemic P a -

ligands 304a-c (R = Me, i-Pr and Ph) was developed. These novel ligands were prepared

in three steps from 2-chloro-4-methyl-6,7-dihydro-5H-[l]-p~dine-7-one 269 and a

series of chiral C2-symmetric 1,2-diols 270a-c (R = Me, i-Pr and Ph).

The P,N-ligands 304a-c were first evaluated in the palladium(0)-catalyzed

asymmetric Heck reaction of 2,3-dihydrofuran 307 and phenyltriflate 308. The best and

only successful result was obtained with the P,N-ligand 304a (R = Me). In this case, the

desired reaction product 309 was isolated in reasonable yield (59%) and in moderate

(152) Vineyard, B. D.; Knowles, W. S.; Saback, M. J.; Bachman, G. L.; Weinkauff, D. J. Asymmetric

Hydrogenation. Rhodium Chiral Biphosphine Catalyst. J. Am. Chem. Soc. 1977, 99, 5946.

enantioselectivity (20% ee) (Scheme 4.9.1 .). The remaining two PSJ-ligands 304a,b (R =

i-Pr and Ph) did not catalyze this reaction.

Scheme 4.9.1. Asymmetric Heck Reaction employing the P,N-ligand 304a (R = Me)

Ph2P Me

307 ~e

3.0 rnol % 1.5 rnol % Pd2dba3

+ (i-PrhNEt, benzene, 70 "C, 3 d *

PhOTf 308 (S)-309 (22% ee)

The P,N-ligands 304a-c were subsequently evaluated in the palladium-catalyzed

asymmetric allylic substitution reaction of racemic 3-acetoxy- 1,3-diphenyl- 1 -propene RS-

310 with dimethyl malonate 311. The PSJ-ligands 304a-c were evaluated with three

different sets of reagents that enabled the counter ion of the nucleophile to be varied. The

best result was obtained when the P,N-ligand 304c (R = Ph) was used with cesium

carbonate as the base at 0 O C which afforded the reaction product (R)-312 in high

enantiomeric excess (90%) (Scheme 4.9.2.).

Scheme 4.9.2. Asymmetric Allylic Substitution Reaction employing the P,N-Ligand 304c (R =

Ph)

Me I

Ph Me02C-C02Me 31 1 6.25 mol %

0 Ac t

91 % Ph dPh RS-310 Ph (R)-312 (90% ee)

The P,N-ligands 304a-c were also evaluated in asymmetric iridium(1)-catalyzed

hydrogenation reactions of alkenes. The Ir(I)(P,N-ligand 304a-c)(COD)(TFPB)

complexes 324a-c were prepared upon reaction of iridium cyclooctadiene chloride dimer

with the P,N-ligands 304a-c and then subsequent treatment with NaTFPB to afford the

desired iridium complexes as air- and moisture-stable orange solids. These complexes

were evaluated as chiral catalysts in the asymmetric hydrogenation reactions of 1-

methoxy-4-[(E)-2-phenylprop- 1 -enyl]benzene 328 and methyl a-acetamidocinnamate

332. However, these complexes were catalytically inactive under the reaction conditions

employed.


SYNTHESIS AND E VAL UA TION OF A RELA TED CHIRAL NONRACEMTC C2-SYMMETRIC 2,2'-

BIPYHDYL LEAND

5.1. Introduction

In this chapter, the synthesis of a related chiral nonracemic Cz-symmetric 2,2'-

bipyridyl ligand 333 is described. In this case, the ligand design featured a subtle

modification of the cyclic acetal moiety in that the chirality was installed in the

heterocyclic portion of the bipyridine unit. This differed from the first generation of

chiral 2,2'-bipyridyl ligands 267a-c (Chapter 2) and the P,N-ligands 304a-c (Chapter 4).

In these cases, the source of the chirality of the ligands was provided by the chiral 1,2-

diols 270a-c. The evaluation of the chiral 2,2'-bipyridyl ligand 333 in copper(1)-

catalyzed asymmetric cyclopropanation reactions of alkenes and diazoesters, in

copper(1)-catalyzed asymmetric allylic oxidation reactions of alkenes as well as in

copper(I1)-catalyzed asymmetric Friedel-Crafts alkylation reactions was undertaken.*

It was envisioned that this ligand could be synthesized from the chiral nonracemic

2-chloroacetal 334 by a nickel(0)-mediated homo-coupling reaction. The chiral 2-

(*) Part of the research described in this chapter has been published (or submitted for publication), see: (a)

Lyle, M. P. A.; Draper, N. D.; Wilson, P. D. Enantioselective Friedel-Crafts Alkylation Reactions

Catalyzed by a Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Copper(I1) Complex. Org. Lett. 2005, 7,

901. (b) Lyle, M. P. A.; Wilson, P. D. Synthesis of a New Chiral Nonracemic C2-Symmetric 2,2'-

Bipyridyl Ligand and its Application in Copper(1)-Catalyzed Enantioselective Cyclopropanation Reactions.

Org. Lett. 2004, 6, 855. (c) Lyle, M. P. A.; Wilson, P. D. Asymmetric Allylic Oxidation Reactions

Catalyzed by a Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Copper(1) Complex. Org. Lett. 2005, 7,

0000 (Submitted).

chloroacetal 334 could in turn be prepared from the 2-chloropyrindine 336 by an

asymmetric dihydroxylation reaction and subsequent condensation with 3-pentanone.

This ketone was selected because it is symmetrical and so this would ensure that only a

single diastereoisomer would form upon condensation with the diol. In addition, the

ethyl substituents would be somewhat larger than that would be installed if acetone was

employed as a reaction partner. The 2-chloropyrindine 336 could be prepared from the

acetate 282 by an elimination reaction. The acetate 282 was a key intermediate that was

employed in the preparation of the chiral 2,2'-bipyridyl ligands 267a-c (Chapter 2) and

the P,N-ligands 304a-c (Chapter 4).

Figure 5.1.1. Retrosynthetic analysis of the chiral nonracemic C2-symmetric 2,2'-bipyridyl ligand

333.

5.2. Synthesis of the 2-Chloropyrindine (336)

2-Chloro-4-methyl-5H-[llpyrindine 336 was prepared, as essentially a single

regioisomeric product (>30: I), on heating the acetate 282 briefly in concentrated sulfuric

acid at 120 "C for 10 min. When the reaction was run for 1 h, the ratio of regioisomers

decreased significantly (<lo: 1) which was due to an acid-catalyzed formal 1,3-hydrogen

shift. The ratio of these regioisomeric products was conveniently determined by

inspection of the 'H NMR spectrum. Fu and co-workers have reported a related reaction

in which a functionalized pyrindine was formed as a mixture of regioisomers (2: 1) after

heating the corresponding acetate in sulfuric acid at 125 "C for 1 h.'53

Scheme 5.2.1. Synthesis of the 2-Chloropyrindine 336

5.3. Catalytic Asymmetric Dihydroxylation Reaction of the 2-

Chloropyrindine (336)

The asymmetric dihydroxylation (AD) of the pyrindine 336 with AD-mix$

afforded the diol (+)-335. This involved the reaction of the pyrindine 336 with AD-mix-

p in a mixture of tert-butanol and water (1: 1) at 0 "C for 12 h.154 The crude diol (+)-335

was then directly reacted with 3-pentanone in the presence of a catalytic amount of p-

toluenesulfonic acid monohydrate in benzene at reflux which afforded the chiral acetal

(+)-334 in reasonable overall yield (57%, over two steps). The chiral acetal (+)-334 was

(153) Ruble, J. C.; Fu, G. C. Chiral n-Complexes of Heterocycles with Transition Metals: A Versatile New

Family of Nucleophilic Catalysts. J. Org. Chem. 1996, 61, 7230.

(154) For a review on AD reactions, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic

Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483.

found to have a high enantiomeric excess (90%) upon analytical chiral HPLC analysis

(Daicel Chiracel OD column).

Scheme 5.3.1. Sharpless Asymmetric Dihydroxylation Reaction of the Pyrindine 336

(+)-334 (90% ee)

Reagents and Conditions: (a) AD-mix-/3, t-BuOHIH20 (1:1), 0 "C, 12 h; (b) 3-pentanone, PhH, p-

TsOH (cat.), reflux, 16 h, 57% (over two steps).

The structure of the chloroacetal (+)-334 was assigned on the basis of

spectroscopic evidence. In particular, the mass spectrum displayed the expected

molecular ion peaks for M('~CI + H) and M( '~c~ + H) at 268 and 270, respectively. The

1 H NMR spectrum of the chiral chloroacetal (+)-334 contained the expected resonances

for the two diastereotopic ethyl moieties as well as a coupled C-6 proton signal at 6 =

4.99 ppm and a coupled C-7 proton signal at 6 = 5.41 ppm that were attributable to the

cyclic acetal (Figure 5.3.1 .).

1 Figure 5.3.1. H NMR spectrum of the chiral chloroacetal (+)-334.

The regiochemistry of the chloroacetal (+)-334 was confirmed on inspection of

the NOESY spectrum of this compound. Diagnostic nOe contacts were observed

between the diastereotopic C-5 protons and the protons of the C-4 methyl substituent

(Figure 5.3.2.).

Figure 5.3.2. Diagnostic contacts observed in the NOESY spectrum of the chloroacetal (+)-334.

It was considered that the moderate yield of the diol (+)-335 obtained using the

standard Sharpless asymmetric dihydroxylation reaction conditions could be due to the

slow reaction rate and that exposure of the pyrindine 336 to these reaction conditions for

a long period of time could have led to further detrimental oxidation processes. This

hypothesis was plausible as the mass recovery from the reaction work-up was low and it

appeared that some very polar byproducts were formed.

Sharpless and co-workers have reported an improvement in the rate of the AD

reaction with the chiral ligand (DHQD)2PHAL using methanesulfonamide as an

additive.'55 Using these reaction conditions, the rate and yield of the above reaction were

not improved.

The rate and yield of this AD reaction were improved when it was modified and

performed with 1 mol % of potassium osmate dihydrate and 5 mol % of the chiral ligand

(155) (a) Wang, Z.-M.; Kakiuchi, K.; Sharpless, K. B. Osmium-Catalyzed Asymmetric Dihydroxylation of

Cyclic cis-Disubstituted Olefins. J. Org. Chem. 1994, 59, 6895. (b) Wang, L.; Sharpless, K. B. Catalytic

Asymmetric Dihydroxylation of cis-Disubstituted Olefins. J. Am. Chem. Soc. 1992, 114, 7568.

(DHQD)2PHAL (a ten-fold higher catalyst loading than typically used in AD reactions),

potassium ferricyanide and potassium carbonate in a mixture of tert-butanol and water

(1: 1) at 0 "C for 2 h. The acetal (+)-334 was isolated in an improved yield (81%) and in

the same enantiomeric excess (90%) upon reaction of the crude diol with 3-pentanone

(Scheme 5.3.2.). The rate of the AD reaction was also significantly improved (2 hours

vs. 12 hours reaction time).

Scheme 5.3.2. Modified Sharpless Asymmetric Dihydroxylation Reaction

336 (+)-335 (+)-334 (90% ee)

Reagents and Conditions: (a) 1 rnol % K20s04.2H20, 5 mol % (DHQD)2PHAL, K3Fe(CN)6,

K2CO3, t-BuOHIH20 (1:l) 2 h; (b) 3-pentanone, PhH, p-TsOH (cat.), reflux, 16 h, 81% (over two

steps).

A final optimization attempt concerned the employment of N-methylmorpholine-

N-oxide as the stoichiometric oxidant instead of iron ferricyanide in the latter two step

procedure. In this case, the acetal (+)-334 was isolated in excellent overall yield

( ~ 9 % ) . ' ~ ~ However, the reaction time required was longer (24 h) and the

enantioselectivity of the reaction was significantly compromised (61% ee).

Cyclic cis-alkenes are known to be one of the most challenging substrates in the

Sharpless AD reactions. To the best of our knowledge, the AD reaction on the pyrindine

336 is the highest enantioselectivity (90% ee) that has been reported for a cyclic cis-

(156) Wang, Z.-M.; Sharpless, K. B. A Solid-to-Solid Asymmetric Dihydroxylation Procedure for

Kilogram-Scale Preparation of Enantiopure Hydrobenzoin. J. Org. Chem. 1994,59, 8302.

alkene.15j Hanessian and co-workers have reported that indene can be dihydroxylated

with a simple C2-symmetric chiral ligand derived from (lR,2R)-trans-1,2-

diaminocyclohexane in 80% ee (70% yield). '57 However, the chiral ligand and osmium

tetraoxide were used stoichiometrically in this reaction. For additional comparison, the

AD reaction of indene 338 with AD-mix$ has been reported to afford the corresponding

diol 339 (6S,7R stereochemistry) in only moderate enantiomeric excess (33-40%)

(Scheme 5.3.3.).15'

Scheme 5.3.3. Sharpless Asymmetric Dihydroxylation of lndene 338

AD-mix-p, t-BuOHIH20 (1 :I ), room temperature, 4 h w

HOQ HO

338 339 (33-40% ee)

The origin of the high enantioselectivity (90% ee) in the AD reaction of the

pyrindine 336 are unclear. However, it is reasonable to suggest that the pyridine nitrogen

causes an increase in enantioselectivity in the AD reaction of the pyrindine 336 (90% ee)

relative to indene 338 (33-40% ee) because of a secondary coordinative interaction to the

osmium tetraoxide of the catalytic species or to a spectator molecule of osmium

tetraoxide. Enhancements in enantioselectivity have been attributed to secondary

coordinative effects for AD reactions of allylic alcohol substrate^.'^^ In support of this

hypothesis, it was observed that the regioisomeric pyrindine 337 undergoes an AD

(157) Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sanceau, J.-Y.; Bemani, Y. Asymmetric

Dihydroxylation of Olefins With a Simple Chiral Ligand. J. Org. Chem. 1993, 58, 1991.

(158) Spivey, A. C.; Hanson, R.; Scorah, N.; Thorpe, S. J. Sharpless Asymmetric Dihydroxylation: Effect

of Alkene Structure on Rates and Selectivity. J. Chem. Ed. 1999, 76,655.

(159) Hale, K. J.; Manaviazar, S.; Peak, S. A. Anomalous Enantioselectivity in the Sharpless Catalytic

Asymmetric Dihydroxylation Reaction of 1,l-Disubstituted Ally1 Alcohol Derivatives. Tetrahedron Lett.

1994, 35,425.

reaction in low enantiomeric excess (16%). This result was obtained when an AD

reaction of a mixture of the regioisomeric pyrindines 336 and 337 (-8: 1) was performed

(Scheme 5.3.4.). The acetals (+)-334 and 340 were separable by column chromatography

and the enantiomeric excess of the regioisomeric acetal340 was determined by analytical

chiral HPLC (Daicel Chiracel OD column).

Scheme 5.3.4. Sharpless Asymmetric Dihydroxylation of an -8:l Mixture of the Regioisomeric

Pyrindines 336 and 337

)pCI 0 (+)-334 (-90% ee) ,p

Et Et

E t X ' N/ 0 340 (16% ee)

(336:337, -8:l)

Reagents and Conditions: (a) 1 mol % K2OsO4.2H20, 5 mol % (DHQD)2PHAL, K3Fe(CN)6,

K2CO3, t-BuOHIH20 (1:1), 0 ' C , 2 h; (b) 3-pentanone, PhH, p-TsOH (cat.), reflux, 16 h (product

yields not determined).

The absolute stereochemistry of the diol (+)-335 was not determined definitively

but the assignment (6S,7R) was based on the well-established predictability of the

Sharpless AD reaction and on the stereochemical outcome of the asymmetric reactions

that are described later in this chapter. In the figure below, the proposed transition state

341 for the AD reaction of the 2-chloropyrindine 336 with osmium tetraoxide and

(DHQD)2PHAL is depicted (Figure 5.3.3.). The proposed transition state 341 could be

rationalized on the basis of the minimization of steric interactions between the substrate

and the catalyst which would lead to a product with (6S,7R)-stereochemistry.

OMe

(6S,7R)-(+)-335

Figure 5.3.3. The proposed transition state for the AD reaction of the 2-chloropyridine 336.*


Ligand I(+)-3331 from the Chloroacetal [(+)-3341

The new chiral nonracemic and C2-symmetric 2,2'-bipyridyl ligand (+)-333 was

prepared by a nickel(0)-mediated coupling reaction of the acetal (+)-334 in 84% yield

(Scheme 5.4.1 The reaction conditions involved heating a solution of the acetal (+)-

334 (90% ee) in N,N-dimethylformamide in the presence of the

tetrakis(triphenylphosphine)nickel(O) (formed in sitzl upon reduction of nickel(I1)

chloride hexahydrate with zinc dust in the presence of triphenylphosphine) which

afforded the 2,2'-bipyridyl ligand (+)-333 as a white crystalline solid in good yield

(84%).*

(*) The methyl substituent of the pyrindine 336 has been removed in the transition state 341 for clarity.

(*) The enantiomeric 2,2'-bipyridyl ligand (-)-333 was also prepared in 53% yield (unoptimized) from the

enantiomeric acetal (-)-334 which was prepared from the pyrindine 336 using AD-mix-a in the Sharpless

asymmetric dihydroxylation reaction.

Scheme 5.4.1. Synthesis of the 2,2'-Bipyridyl Ligand (+)-333

NiC12(H20)6, PPh3, Zn dust, DMF, 60 "C, 4 h

(+)-334 (90% ee) (+)-333 (>99% ee)

The mass spectrum of the chiral 2,2'-bipyridyl ligand (+)-333 displayed the

expected molecular ion peak for M[(+)-333 + HI at 465. The 'H NMR spectrum of the

chiral 2,2'-bipyridyl ligand (+)-333 displayed the expected low field resonance for the

equivalent C3 and C3' protons at B = 8.30 ppm which is diagnostic of a 2,2'-bipyridine

moiety (Figure 5.4.1 .).

1 Figure 5.4.1. H NMR spectrum of the chiral nonracemic C2-symmetric 2,2'-bipyridyl ligand (+)-

The 13c NMR spectrum again clearly indicated the C2-symmetry of this 2,2'-

bipyridyl ligand (+)-333 (Figure 5.4.2.). This compound has a molecular formula of

C28H36N204 and fourteen signals were observed in the I3c NMR spectrum.

I ' I ' --

, , ' I , I -n-.- , 7 I , , , I I I ' T - r r

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm (fl)

Figure 5.4.2. 1 3 c NMR spectrum of the chiral nonracemic C2-symmetric 2,2'-bipyridyl ligand (+)-

333.

A small amount of the corresponding meso-bipyridine 342 was also isolated from

this reaction by flash chromatography (-5%). The enantiomeric purity of the desired

bipyridyl ligand (+)-333 was determined by analytical chiral HPLC and found to be

greater than 99% ee. Since the starting chiral2-chloroacetal (+)-334 had an enantiomeric

excess of 90%, this indicated that a significant enrichment of the enantiomeric purity of

the chiral material had occurred in this coupling reaction. It was hypothesized that the

enrichment was due to the conversion of the minor enantiomer of the starting material to

the diastereoisomeric meso-bipyridine 342 which was then separated from the desired

2,2'-bipyridine (+)-333 by flash chromatography (Figure 5.4.3.).

(+)-334 (-)-334

95:5 enantiomeric ratio

(+)-333, (84% yield, >99% ee)

meso-342 (-5% yield)

Figure 5.4.3. Enrichment of enantiomeric purity in the homo-coupling reaction of the 2-

chloroacetal (+)-334.

5.5. Synthesis of the Tetrahydroquinoline (344)

Given the high enantioselectivity that was obtained in the AD reaction of the 2-

chloropyrindine 336, it was decided to prepare the corresponding dihydroquinoline, 2-

chloro-4-methyl-6,7-dihydroquinoline 345. This precursor could then be elaborated to

the corresponding 2,2'-bipyridine ligand 343 using a similar synthetic route to that was

used to prepare the pyrindine 336 (Figure

Me Me p 0 0 Y

Et' Et

343 344

Figure 5.5.1. Retrosynthetic analysis of the 2,2'-bipyridine ligand 343.

Thus, the 2-hydroxypyridine 347 was prepared on a multi-gram scale by heating

equimolar amounts of cyclohexanone, ethyl acetoacetate and ammonium acetate at reflux

for 8 hours following which the highly crystalline product crystallized from the reaction

mixture (Scheme 5.5.1.).'l6 Subsequent recrystallization from ethanol afforded the 2-

hydroxypyridine 347 in 18% yield. The IR spectrum of the 2-hydroxypyridine 347 had a

characteristic broad 0-H peak at 3426 cm-'. In the 'H NMR spectrum, the C-3 aromatic

proton resonance appeared at 6 = 6.25 ppm which again indicated that the 2-

hydroxypyridine 347 existed mainly as the aromatic tautomer.

Scheme 5.5.1. Synthesis of the Dihydroquinoline 345 and Its Sharpless Asymmetric

Dihydroxylation Reaction

OR 349 (R = Ac) 1

0 0 x Et Et

344 (5% ee)

Reagents and Conditions: (a) ethyl acetoacetate, NH40Ac, reflux, 8 h, 18%; (b) PhP(O)CI2, 160

"C, 16 h, 84%; (c) H202, H20, AcOH, 80 OC; (d) Ac20, rt, 1 h then 100 "C, 4 h, 77% (over two

steps); (e) LiOH, THF, H20, rt, 16 h; (f) polyphosphoric acid, 100 "C, 30 min, 83% (over two

steps); (g) AD-mix-P , t-BuOHIH20 (1:1), 0 "C, 12 h; (b) 3-pentanone, PhH, p-TsOH (cat.), reflux,

16 h, 79% (over two steps)

The 2-hydroxypyridine 347 was then heated with phenylphosphonic dichloride at

160 "C for 16 hours which afforded the 2-chloropyridine 348 in 84% yield. The mass

spectrum of this compound displayed molecular ion peaks for M ( ~ ~ c ~ + H) and M ( ~ ~ c ~ +

H) at 182 and 184, respectively, in a 3: 1 ratio. Subsequent oxidation of this compound

with 30% aqueous hydrogen peroxide in acetic acid at 80 "C for 16 hours afforded the

corresponding pyridine N-oxide. This compound was then heated with acetic anhydnde

at 100 "C for 4 hours which afforded the acetate 349 in good yield (77%, over two

steps).'19 It was then attempted to convert the acetate 349 to the dihydroquinoline 345 by

employment of the same reaction conditions used in the synthesis of the pyrindine 336

(concentrated sulfuric acid, 120 "C, 10 min). However, under these reaction conditions

none of the desired reaction product was isolated and it appeared that a significant

amount of polymeric material had formed. Thus, the acetate 349 was hydrolyzed with

lithium hydroxide in a mixture of tetrahydrofuran and water (3: 1) at room temperature for

16 h which afforded the alcohol 350. The crude alcohol 350 was then heated with

polyphosphoric acid at 120 "C for 30 min which afforded the desired dihydroquinoline

345 in good yield (83%, over two steps).I6O The AD reaction of the dihydroquinoline 345

with AD-mix$ in a mixture of tert-butanol and water (1: 1) at 0 "C for 12 h afforded the

corresponding diol in good yield (86%). Subsequent condensation of this diol with 3-

pentanone in the presence of a catalytic amount ofp-toluenesulfonic acid monohydrate in

benzene at reflux afforded the chiral acetal 344 in very good yield (92%). However,

analytical chiral HPLC analysis (Daicel Chiralcel OD column) showed that the acetal344

(160) Aganval, S. K.; Boyd, D. R.; Davies, J. H.; Hamilton, L.; Jerina, D. M.; McCullough, J. J.; Porter, H.

P. Synthesis of Arene Oxide and trans-Dihydrodiol Metabolites of Quinoline. J. Chem. Soc., Perkin Trans.

1 1990, 1969.

had been formed in low enantiomeric excess (5%). Thus, the AD reaction of the

dihydroquinoline 345 is much less enantioselective that the AD reaction of the pyrindine

336.

The low enantioselectivity of the AD reaction of the dihydroquinoline 345 (5% ee)

is surprising when it is compared to the notably high enantioselectivity of the AD

reaction of the pyrindine 336 (90% ee). For comparison, the AD reaction of

dihydronapthalene 351 with AD-mix$ has been reported to afford the corresponding diol

352 in low enantiomeric excess (7%) (Scheme 5.5.2.).'55 Based on the results obtained in

the AD reactions of the pyrindine 336 and the dihydroquinoline 345 as well as the

literature reports for indene 338 and dihydronapthalene 351, it appears that five-

membered ring cyclic alkenes lead to dihydroxylated products in significantly higher

enantioselectivities than do six-membered ring cyclic alkenes.

Scheme 5.5.2. The AD reaction of Dihydronapthalene 351 with AD-mix-P

351 352 (7% ee)

5.6. Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in Copper(1)-

Catalyzed Asymmetric Cyclopropanation Reactions of Alkenes

With the new chiral nonracemic and C2-symmetric 2,2'-bipyridyl ligand (+)-333

in hand, the evaluation of this chiral ligand in catalytic asymmetric synthesis was

undertaken by executing a series of copper(1)-catalyzed asymmetric cyclopropanation

reactions (Table 5.6.1 .).

Table 5.6.1. Asymmetric Cyclopropanation Reactions of Alkenes 353a-e

>OZR3 1.25 mol % Cu(OTq2, N2 354a-c 1.5 mol % L* [(+)-333 or (-)-3331

1.5 rnol % PhNHNH,, CH2CI2, + co2R3

room temperature, 15 h t R2//I 355a-g

R2 b

R'

R' 353a-e

entry L* R' R2 R3 product trans:cis yield (%) % ee (trans)

According to standard literature procedures, the active copper(1)-catalyst was

generated in situ by reduction of the complex formed between 1.25 mol % of copper(I1)

triflate and 1.5 mol % of the chiral ligand (+)-333 with phenylhydrazine. The

asymmetric cyclopropanation reactions were carried out at room temperature in

dichloromethane and involved the slow addition of the diazoesters 354a-c (over -3 h) to

solutions of alkenes 353a-e and the preformed catalyst. Of note, the diazoesters 354a-c

were again employed as the limiting reagent to minimize homo-coupling reactions of the

diazoesters that would form the corresponding fumarates. The diastereoselectivities of

(161) For example, see: Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani,

P.; KoEovsky, P. Synthesis of New Chiral 2,2'-Bipyridine Ligands and their Application in Copper-

Catalyzed Asymmetric Allylic Oxidation and Cyclopropanation. J. Org. Chem. 2003, 68,4727.

the cyclopropanation reactions were determined by analysis of the 'H NMR spectra of the

crude reaction products. The yields reported in the table are the combined yields of the

chromatographically separated trans- and cis-cyclopropanes. The enantioselectivities of

the trans-cyclopropanes were determined by analytical chiral HPLC (Daicel Chiracel OD

column) following reduction to the corresponding primary alcohols with lithium

aluminum hydride. The enantioselectivities of the cis-cyclopropanes were again not

determined because these compounds were the minor reaction products and that the

enantiomers of these particular compounds were difficult to separate by analytical chiral

HPLC (Daicel Chiracel OD column).

In all instances, the catalytic system was found to be active and afforded the

desired reaction products 355a-g in good yield (49-8 1 %). The asymmetric

cyclopropanation reaction of styrene 353a with ethyl diazoacetate 354a afforded the

cyclopropane 355a in good yield (74%), diastereoselectivity (80:20) and

enantioselectivity (82% ee) (entry 1). This result compares favorably with several other

known chiral2,2 '-bipyridyl ligands.73 An improvement of the diastereoselectivity of this

reaction was achieved when benzyl and tert-butyl diazoacetate 354b-c were used to

prepare the corresponding cyclopropanes 355b-c (dr = 92:8 and 93:7, respectively)

(entries 2 and 3). Moreover, very high enantioselectivity (92% ee) was also recorded for

the reaction of styrene 353a with tert-butyl diazoacetate 354c (entry 3). The absolute

stereochemistry of the cyclopropane 355a was assigned as (1 R,2R) by comparison of the

optical rotation with literature values.'" The enantiomeric ligand (-)-333 was used to

(162) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Highly Enantioselective Cyclopropanantion with Co(I1)-

Salen Complexes: Control of cis- and trans-Selectivity by Rational Ligand Design. Adv. Synth. Catal.

2001,343, 79.

prepare the cyclopropane ent-35% in nearly identical enantioselectivity (93% ee), which

also illustrated the observed reproducibility of these asymmetric cyclopropanation

reactions (entry 4). It is known that the enantioselectivity of cyclopropanation reactions

of styrene derivatives are susceptible to electronic effect^.^"^^ Thus, it was found that the

asymmetric cyclopropanation of an electron rich substrate, p-methoxystyrene 353b, with

ligand (+)-333 afforded the corresponding cyclopropane 355d in only moderate

enantiomeric excess (71%) (entry 5). However, the electron poor substrate p-

fluorostyrene 353c afforded the corresponding cyclopropane 355e in exceptionally high

enantiomeric excess (99%) (entry 6). The latter result, to the best of our knowledge, is

the highest reported enantioselectivity for an asymmetric cyclopropanation reaction with

a chiral bipyridyl ligand. The ligand (+)-333 was also used to cyclopropanate a terminal

alkene, 4-phenyl-1-butene 353d, in good enantiomeric excess (83%) (entry 7) as well as a

1,l -disubstituted alkene, 1,l -diphenylethene 353e, in moderate enantiomeric excess

(72%) (entry 8).

The stereochemical outcome of these asymmetric cyclopropanation reactions can

be rationalized in terms of minimization of steric interactions between the reacting

species and the copper(1)-complex of the bipyridyl ligand (+)-333 (Figure 5.6.1 Four

modes of approach of the styrene derivatives to the chiral copper carbene intermediate

can be envisioned in the depicted front on view. The energetically favoured approaches

of the styrene derivatives to the copper carbene intermediate 356 would be those in which

the large aromatic substituents of the styrene derivatives are on the opposite face as the

(163) Doyle, M. P. Chiral Catalysts for Enantioselective Carbenoid Cyclopropanation Reactions. Red .

Trav. Chim. Pays-Bas 1991,110, 305.

chiral acetal moieties of the ligand (+)-333 in that this would minimize of steric

interactions (as depicted by the curly arrows).

Lower Energy Mode

(1 R,2R)-trans-355 (1 S,2R)-cis-355

[Major-path (a)] [Minor-path (b)]

Higher Energy Mode

[Major-path (a)] [Minor-path (b)]

Figure 5.6.1. Rationalization of the stereochemical outcome of the asymmetric cyclopropanation

reactions based on the minimization of steric interactions between the catalyst and the reacting

species.

The approaches of the styrene derivative in which the aromatic substituent is on

the opposite side as the ester moiety of the carbene complex would lead to the major

trans-cyclopropane product 355 [path (a)]. Furthermore, from the depictions presented it

can be appreciated that the size of the ester moiety in the copper carbene intermediate

would influence the level of diastereoselectivity of these reactions (which is

experimentally observed). The high levels of stereoinduction recorded can be

rationalized in terms of the structural rigidity that is provided by the chiral acetal moieties

of the C2-symmetric bipyridyl ligand. Of note, disubstituted chiral bisoxazoline ligands

can provide improved enantioselectivities in AC reactions relative to monosubstituted

bisoxazoline ligands. 164

As a result of the excellent results obtained with the new chiral nonracemic Cz-

symmetric 2,2'-bipyridyl ligand (+)-333 in copper(1)-catalyzed asymmetric

cyclopropanation reactions, it was decided to evaluate this ligand in other catalytic

asymmetric reactions. In the following section, the evaluation of this ligand in

copper(I1)-catalyzed asymmetric Friedel-Crafts alkylation reactions is described.

5.7. Asymmetric Copper(I1)-Catalyzed Friedel-Crafts Alkylation

Reactions

The Friedel-Crafts (F-C) alkylation reaction is one of the oldest known organic

transformations to employ Lewis acid catalysis and it is a particularly versatile carbon-

carbon bond formation rea~tion.'"~~'" In the mid-1980's the first examples of

asymmetric F-C reactions were reported in the 1i tera t~re . l~~ The asymmetric F-C

reactions can be divided into two categories: (1) asymmetric 1,2-addition of electron rich

(164) Doyle, M. P. Asymmetric Addition and Insertion Reactions of Catalytically-Generated Metal

Carbenes. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000,

Chapter 5.

(165) (a) Friedel, C.; Crafts, J. M. R. Hebd. Seances Acad. Sci. 1877, 84, 1392. (b) Friedel, C.; Crafts, J. M.

R. Hebd. Seances Acad. Sci. 1877,84, 1450.

(166) Olah, G. A.; Khrisnamurti, R.; Prakash, G. K. S. In Comprehensive Organic Synthesis, 1'' ed.;

Pergamon: New York, 1991, Vol. 3, pp 293-339.

(167) (a) Bigi, F.; Casiraghi, G.; Casnati, G.; Satori, G. Asymmetric Electrophilic Substitution on Phenols.

Enantioselective ortho-Hydroxyalkylation Mediated by Chiral Alkoxyaluminum Chlorides. J. Org. Chem.

1985, 50, 5018. (b) Erker, G.; van der Zeijden, A. A. H. Enantioselective Catalysis with a New Zirconium

Trichloride Lewis Acid Containing a "Dibornacyclopentadienyl" Ligand. Angew. Chem., Int. Ed. 1990,29,

5 12.

aromatic systems to carbonyl groups; and (2) asymmetric 1,4-additon of electron rich

aromatic systems to a,/?-unsaturated carbonyl compounds (Figure 5.7.1 .).

1,2-addition to a carbonyl *

1,4-addition to an a,gunsaturated carbonyl

R Ar-H + R

Figure 5.7.1. Possible strategies in the asymmetric Friedel-Crafts alkylation reactions of

activated aromatic compounds.

Recently, Jerrgensen and co-workers have pioneered the catalytic enantioselective

F-C reaction of activated aromatic compounds with electron deficient carbonyl

compounds using the chiral bisoxazoline copper(I1) complex 363 as the catalyst (Scheme

5.7.1.) . '~~ In particular, Jerrgensen has described that the F-C reactions of activated

aromatic compounds 357 with ethyl glyoxylate 358 affords aromatic mandelic esters 359

in high enantiomeric excess (77-95%) and also that the F-C reactions of heteroaromatic

compounds, such as indole 360, with ethyl 3,3,3-triflouropyruvate 361 afforded the

corresponding heteroaromatic hydroxytrifluoromethyl esters 362 in high enantiomeric

excess (83-94%).

(168) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jarrgensen, K. A. Catalytic, Highly Enantioselective

Friedel-Crafts Reactions of Aromatic and Heteroaromatic Compounds to Trifluoropyruvate. A Simple

Approach for the Formation of Optically Active Aromatic and Heteroaromatic Hydroxy Trifluoromethyl

Esters. J. Org. Chem. 2001, 66, 1009. (b) Gathergood, N.; Zhuang, W.; Jarrgensen, K. A. Catalytic

Enantioselective Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate: A Simple Procedure

for the Synthesis of Optically Active Mandelic Acid Esters. J. Am. Chem. Soc. 2000, 122, 12517.

Scheme 5.7.1. Catalytic Asymmetric Friedel-Crafts Reactions of Activated Aromatic Compounds

Catalyzed by the Chiral Copper(l1) bis(0xazoline) Complex 363 (2001)

10 mol % complex 363, THF or CH2CI2 t pCOzE

Me2N /

358 Me2N

357 359 (77-95% ee)

10 mol % complex 363, & THF or CHpC12 t a; C02Et

11.1 R3 361

R~ , R~

360 362 (83-94% ee)

Jnrrgensen and co-workers have also reported the enantioselective F-C reactions of

indoles 364 with the &unsaturated-a-ketoester 365 employing the chiral bisoxazoline

copper(I1) complex 363 which afforded the 1,4-addition products 366 (Scheme 5.7.2.).'69

(169) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jarrgensen, K. A. Catalytic Asymmetric Friedel-Crafts

Alkylation of P,y-Unsaturated a-Ketoesters: Enantioselective Addition of Aromatic C-H Bonds to Alkenes.

Angew. Chem., Int. Ed. 2001,40, 160.

Scheme 5.7.2. Catalytic Enantioselective Michael Addition of lndoles to the p,y-Unsaturated a-

Keto Ester 365 Catalyzed by the Chiral Copper(l1) Bisoxazoline Complex 363 (2001)

10 mol % complex 363, Et20 or CH2CI2

H 0 R3

Ph -C02Me 365 366 (60-99.5% ee)

5.8. Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in Copper(I1)-

Catalyzed Asymmetric Friedel-Crafts Alkylation Reactions

The ligand (+)-333 was evaluated in the reactions of a series of commercially

available indoles 367a-f with the ethyl and methyl esters of 3,3,3-trifluoropyruvic acid

368a,b (Table 5.8.1.). To the best of our knowledge, this is the first report of the

application of a 2,2'-bipyridyl ligand in catalytic enantioselective F-C reactions.

Table 5.8.1. Asymmetric Friedel-Crafts Alkylation Reactions of lndoles 367a-f

10 mol Oh Cu(OTfl2, R', F3C. pH N "

I 10 mol % L* (+)-333, R2 367a-f Et70. 0 "C. 16 h

entry R1 R2 R3 R4 product temperature ("C) yield (%) ee (%)

1 H H H Et

2 H H H Me

3 H H H Me

4 H H Me Me

5 OMe H H Me

6 No2 H H Me

7 H Me H Me

8 H Me Ph Me

The active copper(I1)-catalyst was generated in situ on reaction of 10 mol % of

copper(I1) triflate and 10 mol % of the 2,2'-bipyridyl ligand (+)-333 which afforded a

colourless solution. It was determined that performing the reactions in ether at 0 OC was

the optimal conditions for the reaction. This was determined after performing

preliminary asymmetric F-C reactions of indole 367a with methyl 3,3,3-trifluoropyruvate

368b. The desired product 369b, was isolated in good yield in both dichloromethane and

tetrahydrofuran at 0 OC but the enantioselectivities were relatively lower in these

instances (28% and 45% ee, respectively).

Under the optimized reaction conditions, the copper(I1)triflate complex of ligand

(+)-333 displayed excellent catalytic activity and the F-C reactions reached completion

within 16 h in all instances. The yields reported in the table are of the pure reaction

products after isolation by flash chromatography. The enantioselectivity of the reactions

were determined by analytical chiral HPLC (Daicel Chiracel OD column).

The F-C reaction of indole 367a with ethyl 3,3,3-trifluoropyruvate 368a afforded

the known product 369a in good yield (68%) and in good enantiomeric excess (74%)

(entry 1). The absolute stereochemistry of the reaction product 369a was assigned as (S)

on comparison of the optical rotation with a literature value.'68

The F-C reaction of indole 367a with methyl 3,3,3-trifluoropyruvate 36813

afforded the product 369b in similar yield (77%) but in significantly higher enantiomeric

excess (90%) (entry 2). This result compares favorably with the copper(I1) triflate

bisoxazoline complex catalyzed reactions reported by Jsrgensen and co-workers for a

range of substrates (83-94% ee).'68 Of note, it was assumed that the absolute

stereochemistry of the reaction product 36913 was (S) in that it is reasonable to expect that

the alternative use of the methyl ester of 3,3,3-triflouropyruvic acid 36813 would not

effect the stereochemical outcome of the F-C reaction. There was no fbrther

enhancement of enantioselectivity on repeating the above experiment at a lower

temperature (- 10 "C) (entry 3). Thus, methyl 3,3 ,-trifluoropyruvate 36813 was used

exclusively in the subsequent experiments and the reactions were performed at 0 OC.

The F-C reaction of 2-methylindole 367b again afforded the corresponding

product 369c in high enantiomeric excess (86%) (entry 4). The electron-rich substrate, 5-

methoxyindole 367c, afforded the product 369d in good enantiomeric excess (72%)

whereas the electron-poor substrate, 5-nitroindole 367d, afforded the product 369e in

slightly lower enantiomeric excess (60%) (entries 5 and 6, respectively). Surprisingly, 1-

methylindole 367e and 1-methyl-2-phenylindole 367f afforded the corresponding

products 369f and 369g in low enantiomeric excess (1 8%) (entries 7 and 8, respectively).

Thus, it is evident that the substitution of the hydrogen atom of the indole nitrogen has a

detrimental effect on the enantioselectivity of the F-C reaction. This result is in contrast

to the copper(I1) triflate bisoxazoline complex catalyzed F-C reactions in which

substitution of the indole nitrogen does not lower the enantioselectivity of the r e a ~ t i 0 n . I ~ ~

Further experimentation is required to determine the origin effect. However, these results

do suggest that the indole N-H bond is involved in the reaction transition state or that

detrimental steric factors are at play in these particular catalytic F-C reactions.

The 2,2'-bipyridine (+)-333 was also evaluated in the conjugate addition

reactions of the indole 367a and 3-methoxyphenol 371 to (3E)-2-0x0-4-phenyl-3-

butenoic acid methyl ester 365. 169,'70 In the case of the indole 367, the conjugate addition

product 370 was formed in excellent yield (97%) and good enantiomeric excess (59%)

when the reaction was performed in ether at -78 "C for 16 hours (Scheme 5.8.1.). The

absolute stereochemistry of the major conjugate addition product 370 was assigned as (S)

based on comparison of the optical rotation with a literature ~ a 1 u e . l ~ ~

(170) van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.; Jarrgensen, K. A. Formation of

Optically Active Chrornanes by Catalytic Asymmetric Tandem oxa-Michael Addition-Friedel-Crafts

Alkylation Reactions. Org. Biomol. Chem. 2003, 1, 1953.

Scheme 5.8.1. The Asymmetric Conjugate Addition Reaction of lndole 367a to the P,y-

Unsaturated a-Keto Ester 365

367a N H 10 m01 % Cu(OTfh, 10 mol% L* (+)-333, Ph H 0

Et20, -78 "C, 16 h C02Me +

97% H

370 (59% ee)

In the case of the reaction with 3-methoxyphenol, the reaction was performed in

toluene in the presence of N,N-dimethylaniline at 0 O C for 16 h (Scheme 5.8.2.). In this

instance, the product of the initial conjugate addition reaction underwent a subsequent

intramolecular F-C reaction to afford the novel chromane derivative 372, as a single

diastereoisomer, in moderate enantiomeric excess (42%) and in good yield (62%). The

absolute stereochemistry of the chromane product 372 is not known. However, it is

assumed that the major product of this reaction has the same stereochemistry (at C2) as

that observed for the major conjugate addition product 370.

Scheme 5.8.2. The Conjugate Addition Reaction of 3-Methoxyphenol 371 to the P,y-Unsaturated

a-Keto Ester 365

Me0 OH 10 mol % Cu(OTfh, 10 mol% L* (+)-333,

372 (42% ee)

The product is formed via tandem conjugate additionlintramolecular Friedel-Crafts alkylation reactions

In order to gain insight into the structure of the active catalyst in the above

reactions, a copper(I1) chloride complex was prepared by heating equimolar amounts of

the 2,2'-bipyridyl ligand (+)-333 and anhydrous copper(I1) chloride in a mixture of

ethanol and dichloromethane (1:l). Yellow crystals of the copper(I1) chloride (+)-333

complex that were suitable for X-ray crystallography were obtained on recrystallization,

by slow evaporation of the solvent, from a mixture of ethanol and dichloromethane (2: 1).

An ORTEP representation of the copper(I1) chloride (+)-333 complex is shown

below (Figure 5.8.1 .).* It was found that, in the solid state, the ligands adopt a geometry

that lies between tetrahedral and square-planar around the copper atom (bond angles:

C11 -CU-N1 = 138.12", C11 -Cu-N2 = lO3.12", C12-CU-N2 = 1 37.90•‹, C12-CU-N1 =

101.38", C11-Cu-C12 = 103.12", Nl-Cu-N2 = 80.86") In this structure, the chloride

(*) The X-ray structure determination of the copper(I1) chloride (+)-333 complex was performed by Mr.

Neil D. Draper at Simon Fraser University.

ligands are tilted away from the large cyclic acetal moieties of the C2-symmetric 2,2'-

bipyridyl ligand (+)-333. The bond lengths of the copper atom to the chlorine atoms (C11

and C12) were found to be 2.2 100 and 2.2054 A, respectively. Complete tabulated bond

angles and bond lengths from the X-ray crystal structure of the copper(I1) chloride ligand

(+)-333 complex are provided in the experimental section of this thesis.

Figure 5.8.1. ORTEP representation of the CuC12.1igand (+)-333 complex.'

Similar structural observations have been recorded for several copper(I1) chloride

bisoxazoline ~ o r n ~ l e x e s . ' ~ ' For comparison, an ORTEP representation of the copper(I1)

(*) The thermal ellipsoids are drawn at a 25% probability level for clarity.

chloride tert-butyl bisoxazoline complex prepared by Jmgensen and co-workers is shown

below (Figure 5.8.2.). Again, the ligands are found to adopt a geometry around the

copper atom that lies between tetrahedral and square planar. In addition, the chloride

ligands in this structure are tilted away from the bulky tert-butyl substituents of the C2-

symmetric bisoxazoline ligand.

Figure 5.8.2. ORTEP representation of a CuCI,-tert-butyl bisoxazoline complex.'

In order to rationalize the stereochemical outcome of the copper(I1)-catalyzed

asymmetric F-C reactions of the indoles 367a-f with methyl 3,3,3-trifluoropyruvate 368b,

(171) Thorhaugc, J.; Roberson, M.; Hazell, R. G.; Jsrgensen, K. A. On the Intermediates in Chiral

his(Oxazo1ine) copper(I1)-Catalyzed Enantioselective Reactions-Experimental and Theoretical

Investigations. Chml. ELK J. 2002, 8, 1888 and references thercin.

(*) The thermal ellipsoids are drawn at a 25% probability level for clarity. The crystallographic data for

this complex were obtained from the Cambridge Crystallogaphic Data Centre (see: ref. 171).

it is postulated that the relatively small a-ketoester 368b coordinates in a bidentate

fashion to the copper centre of the copper(I1) triflate (+)-333 complex in an

approximately square planar geometry (Figure 5.8.3 .). The indoles 367a-f would then be

expected to attack the sterically accessible Re-face of the carbonyl moiety. To rationalize

the opposite facial selectivity for the reaction of indole 367a with the P,y-unsaturated a-

ketoester 365, it is postulated that this larger substrate coordinates in a bidentate fashion

to the copper centre in an approximately tetrahedral geometry and that the P,y-unsaturated

a-ketoester moiety adopts an s-cis conformation. The indole would then be expected to

attack the P,y-unsaturated a-ketoester moiety from the more sterically accessible Si-face

of the complex. The lower enantioselectivity of this process may be attributed to the

conformational flexibility of the P,y-unsaturated a-ketoester moiety or, more simply, to

the fact that the reaction centre is located further from the chiral pocket of the complex.

Square-planar Coordination (Re-Face approach, R = CF3)

R OMe

Tetrahedral Coordination (Si-Face approach R = CHCHPh)

Figure 5.8.3. Square-planar and tetrahedral coordination of the a-ketoester substrates 368a,b

and 365 to the chiral catalyst.

5.9. Evaluation of the 2,2'-Bipyridyl Ligand [(+)-3331 in Copper@)-

Catalyzed Asymmetric Allylic Oxidation Reactions

The chiral2,2'-bipyridyl ligand (+)-333 was also evaluated in copper(1)-catalyzed

asymmetric allylic oxidation reactions of cyclic alkenes 373a-c (n = 1-3) with tevt-

butylperoxy benzoate 374 as the oxidant (Table 5.9.1 .).

Table 5.9.1. Asymmetric Allylic Oxidation Reactions

0 ph,J,o,~t-~~ 374 5 mol % Cu(OTfl2, 5.25 mol % L* (+)-333, 1

0 Ph 5.25 rnol % PhNHNH2, acetone or MeCN, 0 "C or rt

+ 45-76% n (

373a-c (n = 1-3)

Q n( (3 (S)-375a-c (n = 1-3)

entry substrate n solvent temperature yield (%) ee (%)

1 acetone

1 MeCN

2 acetone

2 MeCN

2 acetone

2 MeCN

3 acetone

3 MeCN - - - - - -- -- -

The active copper(1)-catalyst for these reactions was generated in situ by

reduction of the complex formed between 5 mol % of copper(I1) triflate and 5.25 mol %

of the chiral ligand (+)-333 with phenylhydrazine in either acetone or acetonitrile. These

solvents were chosen because they have provided the highest enantioselectivities in

related catalytic systems.65 Following the formation of the catalyst, the red reaction

mixtures were then treated with the stoichiometric oxidant tevt-butylperoxy benzoate 374

and an excess (5 equiv) of the cyclic alkenes 373a-c (n = 1-3). The yields listed in the

table are of analytically pure reaction products that were isolated by flash

chromatography. The enantioselectivity of the reactions were determined by analytical

chiral HPLC (Daicel Chiracel OD column) using hexane:isopropanol (250:l) as the

eluant with a flow rate of 0.5 mllminute and UV detection at h = 220 nm.

The allylic oxidation reaction of cyclopentene 373a (n = 1) in acetone at room

temperature for 24 h afforded the reaction product 375a (n = 1 ) in good yield (64%) and

in moderate enantioselectivity (32% ee) (entry 1). Performing the same reaction in

acetonitrile for 16 h afforded the reaction product 375a (n = 1) in similar yield and

enantioselectivity (69 and 34% ee, respectively) (entry 2). The allylic oxidation reaction

of cyclohexene 373b (n = 2) in acetone at room temperature for 16 h afforded the

reaction product 375b (n = 2) in good yield (67%) and in higher enantiomeric excess

(65%) (entry 3). On switching to acetonitrile as the reaction solvent at room temperature,

the enantioselectivity increased substantially (84% ee) (entry 4). However, in this

instance the reaction rate was slower and the reaction product 375b (n = 2) was isolated

in slightly lower yield (56%) after 72 h reaction time. The excellent room results with

cycohexene 373b (n = 2) as the reaction substrate at room temperature led us to attempt

to increase the enantioselectivity by performing the allylic oxidation reactions at a lower

temperature. When the oxidation reaction of cyclohexene 373b (n = 2) was conducted in

acetone at 0 OC for 48 h, the reaction product 375b (n = 2) was isolated in moderate yield

(51%) and good enantiomeric excess (81%) (entry 5). A fiuther enhancement of

enantioselectivity was observed when the reaction was performed in acetonitrile at 0 OC

for 96 h (91% ee). However, in this case, the yield was slightly compromised (45%)

(entry 6). To the best of our knowledge, these are the highest reported

enantioselectivities in an asymmetric allylic oxidation reaction with a chiral 2,2'-

bipyridyl ligand. The allylic oxidation reaction of cycloheptene 373b (n = 3) in acetone

for 16 h afforded the reaction product 375b (n = 3) in good yield (72%) but only in

moderate enantiomeric excess (36%) (entry 7). When the corresponding reaction was

performed in acetonitrile for 16 h, the reaction product 375b (n = 3) was formed in

similar yield and enantioselectivity (72% and 40% ee, respectively) (entry 8). The

absolute stereochemistry of each of the above reaction products 375a-c (n = 1-3) was

assigned as (S) based on comparison of the optical rotations with literature values.65

These results demonstrated that this asymmetric allylic oxidation reaction was highly

substrate dependant.

The asymmetry of the process is most likely the result of the approach of the

allylic radical 377 (shown for cyclohexene) to one of the less hindered quadrants of the

C2-symmetric copper(I1) benzoate complex 376 that would afford the copper(I1I)

complex 378. This species would then undergo a pericyclic rearrangement (or direct

reductive elimination) to afford the product (59-375b and regenerate the catalytic

copper(1) complex (Scheme 5.9.1 .).

Scheme 5.9.1. Rationalization of the Stereochemical Outcome of the Asymmetric Allylic

Oxidation Reactions based on the Minimization of Steric Interactions between the Catalyst and

the Reacting Species

5.10. Optical Rotary Dispersion Spectrum of the Copper(I1) Chloride

[(+)-3331 Complex

In the process of undertaking the characterization of the copper(I1) chloride (+)-

333 complex, we observed that it possessed a large optical rotation ([a] + 793 [c

0.0029, chloroform]) similar to the optical rotation observed for the C ~ ( 2 6 7 c ) ~ C u C l ~

complex described in Chapter 2. The optical rotary dispersion spectrum for this complex

was also recorded (Figure 5.10.1.). The spectrum was recorded at a concentration of 2.9

mg of the complex in 100 mL of chloroform (4.7 x M) and across a wavelength

range of 200 to 800 nm. The maximum positive specific rotation was + 2.3 x lo4 at 293

nm. The maximum negative specific rotation was - 1.2 x lo4 at 332 nm (the

corresponding circular dichroism spectrum is provided in the appendices of this thesis,

see: Section 9.2.). These values are even higher than the specific rotations observed and

reported for the Cu(267c)2CuCI2 complex in Chapter 2.

20000 -.

15000 - C 0 .- CI

V

589 nm, +J.O r 1 ff V)

-1 WOO - v 332 nm -1.2 s I W

-15000 -I 200 300 400 500 600 700 800

Wavelength (nm)


30000 -

Figure 5.10.1. The optical rotary dispersion spectrum of the copper(l1) chloride (+)-333 complex.

A UV-vis spectrum of the copper(I1) chloride (+)-333 complex that was recorded

2x100

on the same sample as the optical rotary dispersion spectrum showed strong absorbances

293 nm. +2.3 x 10'

at 328 nm (E- 2.0 x lo4 M-' cm-I) and 315 nm (E= 2.0 x lo4 M-I cm-I). NO absorptions

were observed above 400 nm in the UV-vis spectrum.

5.11. Conclusions

The efficient synthesis of the low molecular weight, chiral nonracemic and C2-

symmetric 2,2'-bipyridyl ligand (+)-333 from readily available starting materials was

developed. The chirality of the ligand was installed by a modified Sharpless asymmetric

dihydroxylation reaction of a pyrindine in high enantioselectivity (90% ee). This is the

highest reported enantioselectivity for an asymmetric dihydroxylation reaction of a cyclic

cis-alkene.

The ligand (+)-333 was found to be a highly effective chiral director in the

copper@)-catalyzed asymmetric cyclopropanation reactions of a variety of alkenes with

tert-butyl diazoacetate 354c. Very high diastereoselectivities (>95:5) and

enantioselectivities (up to 99% ee) were observed. The reaction conditions involved the

formation of the catalyst in situ by reduction of the complex formed between 1.25 mol %

of copper(1I) triflate and 1.5 mol % of the chiral ligand (+)-333 with phenylhydrazine.

The best result was obtained in the asymmetric cyclopropanation reaction of p-

fluorostyrene 353c with tert-butyl diazoacetate 354c which afforded the reaction product

355e in exceptionally high enantiomeric excess (99%) (Scheme 5.1 1.1 .). This result is

the highest reported enantioselectivity for an asymmetric cyclopropanation reaction with

a chiral2,2'-bipyridine ligand.

Scheme 5.1 1 .I. Asymmetric Cyclopropanation Reaction employing the C2-Symmetric 2,2'-

Bipyridyl Ligand (+)-333

Me Me

1.25 mol % Cu(OTfh, 1.50 mol % PhNHNH2, r\ room temperature, CH2CI2, 15 h

73%

355e (99% ee)

F 353c

The ligand (+)-333 was also evaluated in the copper(I1)-catalyzed asymmetric

Friedel-Crafts alkylation reactions of a series of substituted indoles 367a-f with the

methyl and ethyl esters of 3,3,3-trifluoropyruvic acid 368a,b. High enantioselectivities

were observed (up to 90% ee). However, it was noted that substitution of the hydrogen

atom of the indole nitrogen had a detrimental effect on the enantioselectivity of the

reactions. The reaction conditions involved the formation of the catalyst in situ by

reaction of 10 mol % of copper(11) triflate and 10 mol % of the 2,2'-bipyridyl ligand (+)-

333 in ether. Following catalyst formation, the solutions were cooled to 0 OC and the

indole 367a-f and the methyl or ethyl ester of 3,3,3-trifluoropyruvic acid 368a,b were

added. The best result was obtained for the asymmetric Friedel-Crafts reaction of indole

367a with methyl 3,3,3-trifluoropyruvate 368a which afforded the reaction product 369a

in high enantiomeric excess (90%) (Scheme 5.1 1.2.).

Scheme 5.1 1.2. Asymmetric Friedel-Crafts Reaction employing the C2-Symmetric 2,2'-Bipyridyl

Ligand (+)-33

367a 2 0 10rnolOh

N lit Et F3C QH H

10 mol % Cu(OTfl2, Et20, 0 OC, 16 h * Q+ C02Me

+ 77% N H

369a (90% ee)

We also employed the ligand (+)-333 in related conjugate addition reactions of

the indole 367a and 3-methoxyphenol 371 to (3E)-2-0~0-4-phenyl-3-butenoic acid

methyl ester 365. In the case of indole 367a, the conjugate addition product 370 was

formed in excellent yield (97%) and good enantiomeric excess (59%). In the case of the

reaction with 3-methoxyphenol, the product of the initial conjugate addition reactions

underwent a subsequent intramolecular F-C reaction to afford the novel chromane

derivative 372, as a single diastereoisomer, in moderate enantiomeric excess (42%) and

in good yield (62%). In order to gain insight into the active catalyst in these Friedel-

Crafts alkylation reactions, the copper(I1) chloride (+)-333 complex was prepared and

analyzed by X-ray crystallography. This analysis revealed a distorted square-planar

geometry around the copper(I1) centre. It was observed that the copper(1I) chloride (+)-

333 complex had a remarkably high specific optical rotation. An optical rotary

dispersion spectrum was recorded that displayed a maximum positive specific rotation

was + 2.3 x lo4 at 293 nm and a maximum negative specific rotation was - 1.2 x lo4 at

332 nm.

Finally, the ligand (+)-333 was evaluated in copper(1)-catalyzed asymmetric

allylic oxidation reactions of a series of cyclic alkenes 373a-c using tert-butyl

peroxybenzoate 374. The reaction conditions involved formation of the catalyst in situ

by reduction of the complex formed between 5.0 mol % of copper(I1) triflate and 5.25

mol % of the chiral ligand (+)-333 with phenylhydrazine in either acetone or acetonitrile.

A broad range of enantioselectivities were obtained (32 to 91% ee) that depended on the

substrate and the reaction conditions employed. The best result was obtained in the

asymmetric allylic oxidation reaction of cyclohexene 3738 with tert-butylperoxybenzoate

374 in acetonitrile at 0 OC which afforded the product 375b in high enantiomeric excess

(91 %) (Scheme 5.1 1.3.). This result represents the highest reported enantioselectivity in

an asymmetric allylic oxidation with a chiral 2,2'-bipyridyl ligand. Moreover, the rates

CHAPTER 6: FUTURE WORK

6.1. Synthesis and Evaluation of New Chiral Nonracemic C2-Symmetric

Tripyridine Ligands

In Chapter 2 of this thesis, the synthesis and evaluation of series of chiral

nonracemic C2-symmetric 2,2'-bipyridyl ligands 267a-c (R = Me, i-Pr and Ph) was

described. In the course of subsequent investigations into the use of the 2,2'-bipyridyl

ligands 267a-c as chiral directors it was discovered that these ligands displayed

coordination properties with copper salts that were detrimental to the stereoselectivity of

the copper-catalyzed asymmetric reactions. Future studies with these ligands will involve

their evaluation in asymmetric reactions that are catalyzed by transition metals other than

copper.

In order to further demonstrate the modular and divergent nature of the synthetic

design described in this thesis, future work on this project will also involve the synthesis

and evaluation of a series of chiral nonracemic C2-symmetric tripyridine ligands 379a-c

(R = Me, i-Pr and Ph) (Figure 6.1.1.). These ligands could be prepared from the

corresponding 2-chloropyridines 268a-c and the known bis-stannane 380 by

palladium(0)-catalyzed Stille coupling r ea~ t i 0ns . I~~

(172) Hanan, G. S.; Schubert, U. S.; Volkrner, D.; Riviere, E.; Lehn, J.-M.; Kyritsakas, N.; Fischer, J.

Synthesis. Structure and Properties of oligo-Tridentate Ligands: Covalently Assembled Precursors of

Coordination Arrays. Can. J. Chem. 1997, 75, 169.

379a-c (R = Me, i-Pr and Ph) 268a-c (R = Me, i-Pr and Ph) 380

Figure 6.1.1. Retrosynthetic analysis of the chiral nonracemic C2-symmetric tripyridine ligands


These ligands would then be evaluated as chiral directors in scandium(II1)-

catalyzed asymmetric reactions. Scandium(II1)-catalyzed reactions are particularly

interesting because they are of broad scope and often involve the formation of carbon-

carbon bonds. These reaction types include; Diels-Alder reactions, aza Diels-Alder

reactions, 1,3-dipolar cycloaddition reactions, Friedel-Crafts alkylation reactions and

nucleophilic ring-opening reactions of meso-epoxides. 173

6.2. Modification and Optimization of the Structural Features of the

Chiral Nonracemic C2-Symmetric 2,2'-Bipyridyl Ligand [(+)-3331 and

Evaluation in Asymmetric Reactions

In Chapter 5 of this thesis, the synthesis and evaluation of a new chiral

nonracemic C2-symmetric 2,2'-bipyridyl ligand (+)-333 was described. This ligand was

shown to be an extremely effective chiral director in asymmetric copper(1)-catalyzed

(173) For examples of scandium(II1)-catalyzed asymmetric reactions, see: (a) Kobayashi, S. Scandium

Triflate in Organic Synthesis. Eur. J. Org. Chem. 1999, 15. (b) Evans, D. A.; Scheidt, K. A.; Fandrick, K.

R.; Lam, H. W.; Wu, J. Enantioselective Indole Friedel-Crafts Alkylations Catalyzed by

bis(0xazolinyl)pyridine-Scandium(II1) Triflate Complexes. J. Am. Chem. Soc. 2003, 125, 10780. (c)

Schneider, C.; Sreekanth, A. R.; Mai, E. Scandium-Bipyridine-Catalyzed Enantioselective Addition of

Alcohols and Arnines to meso-Epoxides. Angew. Chem., Int. Ed. 2004, 43,5691.

cyclopropanation reactions, copper(I1)-catalyzed asymmetric Friedel-Crafts alkylation

reactions and copper(1)-catalyzed asymmetric allylic oxidation reactions. Future work on

this project will involve the synthesis of the corresponding mono-N-oxide 382 and N,N'-

dioxide 381 (Figure 6.2.1.). These N-oxides would then be evaluated, for example, as

chiral catalysts in organocatalytic asymmetric aldol reactions.

and

Figure 6.2.1. Retrosynthetic analysis of the chiral pyridine N-oxide 382 and N,N'-dioxide 381.

Future work on this project will also involve the optimization of the ligand

structure by undertaking the synthesis of a series of related ligands 383 in which the

substituents R' and R2 on the chiral cyclic acetal would be varied in order to alter the

shape and electronics of the chiral pocket of the catalytic species. The objective here

would be to improve the level of asymmetric induction in the reaction types that have

already been investigated as well as to study new asymmetric transformations. The C2-

symmetric 2,2'-bipyridyl ligands 383 would be synthesized from the corresponding 2-

chloropyridines 384 using a nickel-mediated homo-coupling reaction (Figure 6.2.2.). The

2-chloropyridines 384 could be prepared from the chiral diol 335 and a series of

symmetrical and unsymmetrical ketones 385 (R' and R2 = various substituents). In the

case of the unsymmetrical ketones 385 (R' # R2), it is anticipated that their condensation

reactions with the diol 335 would be diastereoselective in that the larger substituent

should occupy the less sterically congested convex face of these bicyclic molecules.

Figure 6.2.2. Retrosynthetic analysis of the chiral nonracemic C2-symmetric 2,2'-bipyridyl

ligands 383 (R1 and R2 = various substituents).

Future work on this project will also include the synthesis of a series of the related

chiral nonracemic C2-symmetric tripyridine ligands 386 from the 2-chloropyridines 384

(R1 and R2 = various substituents) and the known stannane 380 via palladium(0)-

catalyzed Stille coupling reactions (Figure 6.2.3.).

Figure 6.2.3. Retrosynthetic analysis of the chiral nonracemic C2-symmetric tripyridine ligands

386 (R1 and R2 = various substituents).

CHAPTER 7: GENERAL CONCLUSIONS

The research work described in this thesis has concerned the concise and modular

synthesis of several new classes of chiral nonracemic ligands and catalysts for use in

asymmetric synthesis. A series of chiral nonracemic acetals 268a-c (R = Me, i-Pr and

Ph) were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[l]pyrindine-7-one 269 and a

variety of C2-symmetric 1,2-ethanediols 270a-c. These acetals were further elaborated,

in a modular fashion, to a series of chiral ligands and catalysts that were then evaluated in

various catalytic asymmetric reactions.

The C2-symmetric 2,2'-bipyridyl ligands 267a-c were prepared in one step from

the acetals 268a-c via a nickel(0)-mediated homo-coupling reaction. Similarly, the

corresponding unsymmetric 2,2'-bipyridyl ligands 271a,b were prepared by a Stille

coupling reaction with 2-(tri-n-butylstanny1)pyridine 272. These ligands were then

evaluated as chiral directors in copper(1)-catalyzed asymmetric cyclopropanation

reactions of styrene and diazoesters. In the course of our investigations it was observed

that the stereoselectivities as well as the yields of the cyclopropanation reactions were

highly dependant on the ratio of the C2-symmetric ligand to copper used. The best result

was obtained in the asymmetric cyclopropanation of styrene with tert-butyl diazoacetate

with the ligand 267b (R = i-Pr) which afforded the reaction product in good

diastereoselectivity (83: 17) and moderate enantioselectivity (44% ee). The unsymmetric

2,2'-bipyridyl ligands 271a,b were found to be poor chiral directors in asymmetric

cyclopropanation reactions. Interestingly, a copper(1) complex of the C2-symmetric

ligand 267c was found to have a large specific optical rotation (+ 1.1 x lo4 at 304 nm).

The chiral pyridine N-oxide 299 and the C2-symmetric 2,2'-bipyridyl N,N-dioxide

301 were prepared by direct oxidation of the chiral acetal 300 and the 2,2'-bipyridyl

ligand 267c, respectively. These chiral N-oxides 299 and 301 were then evaluated as

chiral catalysts in desymmeterization reactions of cis-stilbene oxide with silicon

tetrachloride. The chiral pyridine N-oxide 299 was catalytically active in this reaction

and afforded the desired product in good yield (95%) but in low enantioselectivity (20%

ee). The 2,2 '-bipyridyl N,N'-dioxide did not catalyze this desymmeterization reaction.

A series of Pfl-ligands 304a-c was subsequently prepared in two steps from the

chiral acetals 268a-c by a Suzuki coupling with ortho-fluorophenylboronic acid and

subsequent displacement of the fluoride with the potassium anion of diphenylphosphine.

These ligands were then evaluated as chiral directors in palladium-catalyzed asymmetric

Heck reactions of 2,3-dihydrofuran and phenyltriflate. The best and only result was

obtained with the Pfl-ligand 304a (R = Me) which afforded the desired reaction product

in reasonable yield (59%) and moderate enantioselectivity (20% ee). The ligands were

subsequently evaluated in palladium-catalyzed asymmetric allylic substitution reactions

of racemic 3-acetoxy-1,3-diphenyl- 1 -propene RS-310 with dimethyl malonate 31 1. The

best result was obtained when the Pfl-ligand 304c (R = Ph) was used with cesium

carbonate as the base in dichloromethane at 0 "C which afforded the corresponding

reaction product in excellent yield (91%) and high enantiomeric excess (90%).

A related chiral C2-symmetric 2,2'-bipyridyl ligand (+)-333, that was conceived

by considering a subtle modification to the cyclic acetal moiety of the first generation

ligands, was prepared from 2-chloro-4-methyl-5H-[llpyrindine. This pyrindine was

prepared fiom the acetate 282 that was an intermediate used in the synthesis of the 2,2'-

bipyridines 267a-c and the P,N-ligands 304a-c. The chirality of this ligand was installed

by a highly enantioselective Sharpless dihydroxylation reaction (90% ee). This is the

highest enantioselectivity obtained in a catalytic asymmetric dihydroxylation of a cyclic

cis-alkene. The subsequently elaborated 2,2'-bipyridyl ligand (+)-333 (>99% ee) was

found to be a much more efficient chiral director than the C2-symmetric 2,2'-bipyridyl

ligands 267a-c and the corresponding unsyrnmetric 2,2'-bipyridyl ligands 271a,b that

were described in Chapter 2. It is inferred that the modified ligand (+)-333 did not have a

propensity to form bis-ligated copper(1) complexes. The ligand was evaluated in

copper(1)-catalyzed asymmetric cyclopropanation reactions of various styrenes 353a-g

and diazoesters 354a-c. The best result was obtained in the reaction of para-

fluorostyrene 353c and tert-butyl diazoacetate 354c which afforded the reaction product

in good diastereoselectivity (92:8) and in excellent enantioselectivity (99% ee). This is

the highest enantioselectivity obtained in an asymmetric cyclopropanation reaction with a

chiral bipyridine ligand. The ligand (+)-333 was also evaluated in copper(I1)-catalyzed

asymmetric Friedel-Crafts alkylation reactions. This included the reactions of various

substituted indoles 367a-g with the methyl and ethyl esters of 3,3,3-trifluoropyruvic acid

368a,b. The best result was observed in the reaction of indole 367a with methyl 3,3,3-

trifluoropyruvate 368a which afforded the corresponding reaction product in good yield

(77%) and in good enantioselectivity (90% ee). Finally, the ligand (+)-333 was evaluated

in the copper(1)-catalyzed asymmetric allylic oxidation reaction of cyclic alkenes 373a-c

using tevt-butyl peroxybenzoate 374. A broad range of enantioselectivities were obtained

that depended on the substrate and reaction conditions employed. However good

catalytic activity was observed in all cases. The best result was obtained in the

asymmetric allylic oxidation reaction of cyclohexene 373b in acetonitrile which afforded

the corresponding reaction product in high enantioselectivity (91% ee). A copper(I1)

complex of this ligand was also found to have a high specific optical rotation (+ 2.3 x lo4

at 293 nm).

CHAPTER 8: EXPERIMENTAL SECTION

8.1. General Experimental Details

All non-aqueous reactions were performed under an atmosphere of dry nitrogen in

oven- or flame-dried glassware, unless indicated otherwise. The reaction temperatures

stated were those of the external bath. Diethyl ether (ether) and tetrahydrofuran (THF)

were dried over sodium/benzophenone ketyl and distilled under an atmosphere of dry

nitrogen immediately prior to use. Benzene, toluene, dichloromethane, pyridine, N,N-

diisopropylamine and triethylamine were dried over calcium hydnde and distilled under

an atmosphere of dry nitrogen immediately prior to use. All other solvents and reagents

were purified by standard techniques or used as supplied.174 Brine refers to a saturated

aqueous solution of sodium chloride. Silica gel column chromatography ("flash

chromatography") was carried out using Merck silica gel 60 (230 to 400 mesh).'75

Melting points were measured on a Gallenkamp capillary melting point apparatus and are

uncorrected. Optical rotations were recorded on a Perkin Elmer 341 polarimeter. All

13 proton and carbon and phosphorus nuclear magnetic resonance spectra ('H, C and 3 1 ~

NMR, respectively) were recorded using a Bruker AMX 400 FT spectrometer (operating

13 frequencies: 'H, 400.13 MHz; C, 100.61 MHz; 3 1 ~ , 161.97 MHz) at ambient

temperature. The 'H and I3c chemical shifts (6) for all compounds are listed in parts per

million downfield from tetramethylsilane using the NMR solvent as an internal reference.

The reference values used for deuterated chloroform (CDCl3) were 7.26 and 77.16 ppm

(174) Armarego, W. L. F.; Perrin, D. D. Purijkation of Laboratory Chemicals, 4th ed.; Oxford:

Butterworth-Heinemann, 1997.

(175) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separations with

Moderate Resolution. J. Org. Chem. 1978,43,2923.

for 'H and 13c NMR spectra, respectively. The reference values used for deuterated

benzene (C6D6) were 7.15 and 128.02 ppm, respectively. The reference value used for

deuterated acetone (acetone-D6) was 30.83 ppm for 13c NMR spectra. The 3 ' ~ chemical

shifts (6) are listed in parts per million downfield from phosphoric acid which was

employed as an external reference. Infrared spectra (IR) were recorded as either KBr

pellets (KBr), evaporated films (ef) or as films (neat) using a Perkin Elmer 599B IR

spectrophotometer. Low-resolution mass spectra (MS) were recorded on a Hewlett

Packard 5985 GC-mass spectrometer. The mode of ionization used was chemical

ionization (CI) with isobutane. Matrix-assisted laser desorptiodionization time-of-flight

mass spectra (MALDI-TOF) using 2,5-dihydroxybenzoic acid as the matrix were

recorded on a PerSeptive Biosystems Voyager-DE spectrometer. High-resolution mass

spectra using fast atom bombardment (FAB HRMS) were recorded on a Kratos Concept

IH mass spectrometer. Microanalyses were performed on a Carlo Erba Model 1 106 CHN

analyzer. Analytical chiral high performance liquid chromatography (HPLC) was

performed on a Hewlett Packard Series 1050 instrument. All HPLC separations were

performed on a Daicel Chiracel OD column. Chiral gas chromatography (GC) was

performed on a Varian 3400 instrument. All GC separations were performed on a J & W

Scientific cyclosilb column. Optical rotary dispersion spectra were recorded on a Jasco J-

810 spectropolarimeter. UV-Vis spectra were recorded on a Varian Cary 300

spectrophotometer. All compounds described in this experimental section were fully

characterized (including elemental analyses or high-resolution mass spectrometry).

8.2. Experimental Procedures and Characterization Data Concerning

Chapter 2

A mixture of cyclopentanone (25.2 g, 300 mmol), ethyl acetoacetate (39.0 g, 300

mmol) and ammonium acetate (23.1 g, 300 mmol) was heated at reflux for 8 h. The

reaction mixture was then allowed to cool to room temperature and following dilution

with ether (25 mL) was allowed to stand overnight during which time the product

precipitated from the reaction mixture. The product was isolated by filtration, washed

with ether (50 mL) and recrystallized from ethanol (1 00 mL) to afford the title compound

280 (10.2 g, 23%) as a yellow crystalline solid. M.p. 243-244 OC, ethanol (lit.l16 243-244

"C, ethanol); 'H NMR (CDC13) 6 2.05-2.15 (5H, m, ArCH2CH2 and CH3), 2.66 (2H,

apparent t, J = 7.0 Hz, ArCH2), 2.92 (2H, apparent t, J = 7.6 Hz, ArCH2), 6.22 (1 H, s,

ArH); 13c NMR (CDC13) 620.0, 22.70, 28.7, 31.5, 115.5, 121.2, 149.0, 151.4, 166.3; IR

(KBr) 2912 (broad), 1653, 1621, 1578, 1447, 1425, 1371, 1327,1221,933,901,860 cm-

1 ; MS (CI) m/z (rel. intensity) 150 (M + H, 100).

To phenylphosphonic dichloride (1 .OO mL, 7.08 mmol) was added the pyridine-2-

01 280 (500 mg, 3.36 rnmol) and the resultant mixture was heated in an oil bath at 160 OC

for 16 h. The reaction mixture was then allowed to cool to room temperature and water

(-5 mL) was added dropwise (CAUTION). The acidic reaction mixture was then diluted

with an additional quantity of water (50 mL), neutralized by the careful addition of

potassium carbonate (-1.0 g) and extracted with chloroform (3 x 30 mL). The combined

organic extracts were washed with water (2 x 20 mL), dried over anhydrous magnesium

sulfate and concentrated in vacuo to afford the crude product as a dark brown oil. Flash

chromatography using chloroform as the eluant afforded the title compound 281 (465 mg,

83%) as a white crystalline solid. M.p. 41 -42 OC, chloroform; 'H NMR (CDC13) 62.12

(2H, m, ArCH2CH2), 2.22 (3H, s, CH3), 2.81 (2H, apparent t, J = 7.9 Hz, ArCH2), 2.98

(2H, apparent t, J = 8.3 Hz, ArCH2), 6.90 (lH, s, ArH); 13c NMR (CDC13) 620.1, 22.7,

28.7, 31.4, 115.3, 121.6, 149.0, 151.7, 166.1; IR(KBr) 1654, 1621, 1578, 1425, 1327 cm-

I ; MS (CI) m/z (rel. intensity) 168 (M + H, 100); Anal. Calcd. for C9HloClN: C, 64.48;

H, 6.01; N, 8.36. Found: C, 64.29; H, 5.92; N, 8.30.

To a stirred solution of the chloropyridine 281 (3.00 g, 17.9 mrnol) in glacial

acetic acid (25 mL) was added an aqueous solution of hydrogen peroxide (30% wlw, 8.60

mL, 75.9 mmol) and the resultant mixture was heated at 80 OC for 16 h. The reaction

mixture was then allowed to cool to room temperature and following concentration in

vacuo was diluted with water (100 mL). The slightly acidic solution was neutralized by

the careful addition of potassium carbonate (-1.0 g) and then extracted with chloroform

(3 x 30 mL). The combined organic extracts were washed with water (3 x 15 mL), dried

over anhydrous magnesium sulfate and concentrated in vacuo to afford the corresponding

pyridine N-oxide (3.22 g, 98%) as a white crystalline solid. This material was taken up in

acetic anhydride (25 mL) and the resultant suspension was stirred at room temperature

for 1 h and then heated at 100 OC for 4 h. The reaction mixture was then allowed to cool

to room temperature and was concentrated in vacuo to afford the crude product as a dark

brown oil. Flash chromatography using hexanes:ether (1: 1) as the eluant afforded the

title compound 282 (2.42 g, 60% over two steps) as an orange oil. 'H NMR (CDC13) 6

2.01-2.10 (4H, m, CH3 and ArCH2CHH), 2.27 (3H, s, OAc), 2.58-2.68 (IH, m,

ArCH2CHH), 2.76 (lH, m, ArCHH), 2.94 (lH, m, ArCHH), 6.00 (lH, dd, J = 7.6, 4.6

Hz, CHOAc), 7.06 (lH, s, ArH); 13c NMR (CDC13) 6 18.7, 21 . l , 26.0, 28.2, 30.4, 124.4,

136.1, 147.1, 150.6, 159.9, 170.6; IR (neat) 2946, 1738, 1592, 1571, 1443, 1370, 1235,

1193, 1106, 1050, 890 cm-'; MS (CI) m/z (rel. intensity) 226 (M + H, loo), 166 (38);

Anal. Calcd. for Cl lH~2C1N02: C, 58.54; H, 5.36; N, 6.21. Found: C, 58.79; H, 5.37; N,

6.11.

8.2.4. 7(RS)-2-Chloro-4-methyl-6,7-dihydro-5H-[l/pyrindine- 7-01 (283)

To a stirred solution of the acetate 282 (2.00 g, 8.88 mmol) in

tetrahydr0furan:water (3: 1, 20 mL) was added lithium hydroxide monohydrate (1.49 g,

35.6 mmol) and the resultant solution was stirred at room temperature for 16 h. The

reaction mixture was then diluted with water (15 mL) and extracted with chloroform (3 x

25 mL). The combined organic extracts were washed with brine (1 5 mL) and water (15

mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the

crude product. Flash chromatography using hexanes:ether (1 : 1) as the eluant afforded the

title compound 283 (1.37 g, 94%) as a white crystalline solid. M.p. 100-102 "C;

hexaneslether; 'H NMR (CDC13) 6 1.99-2.16 (lH, my ArCH2CHH), 2.24 (3H, s, CH3),

2.47-2.57 (lH, m, ArCH2CHH), 2.67-2.72 (lH, m, ArCHH), 2.92 (1 H, ddd, J = 13.1, 8.9,

4.0 Hz, ArCHH), 3.82 (1 H, broad s, OH), 5.19 (lH, dd, J = 7.3, 5.8 Hz, CHOH), 6.99

(lH, s, ArH); 13c NMR (CDC13) 6 18.8, 25.9, 32.5, 74.7, 124.0, 135.0, 147.6, 150.4,

164.8; IR (KBr) 1594, 1567, 1445, 1374, 1298, 1191, 1094, 1064, 1019, 965, 925, 888,

861 cm-'; MS (CI) m/z (rel. intensity) 184 (M + H, loo), 166 (20); Anal. Calcd. for

C9HloClNO: C, 58.86; H, 5.49; N, 7.63. Found: C, 58.62; H, 5.62; N, 7.46.

To a stirred solution of oxalyl chloride (57 pL, 0.65 mmol) in dichloromethane (6

mL) at -78 "C was added dimethyl sulfoxide (150 pL, 2.18 mmol) and the resultant

solution was stirred for 10 min. A solution of the alcohol 283 (100 mg, 0.545 mmol) in

dichloromethane (5 mL) was then added via a cannula over the course of 5 min. The

reaction mixture was stirred for an additional 10 min and triethylamine (380 pL, 2.73

mmol) was then added and the reaction mixture was allowed to warm slowly to room

temperature. The reaction mixture was then diluted with ether (30 mL) and washed with

brine (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate and

concentrated in vacuo to afford the crude product. Flash chromatography using

hexanes:ether (1:l) as the eluant afforded the title compound 269 (89 mg, 90%) as a

white crystalline solid. M.p. 149-152 "C; hexaneslether; 'H NMR (CDC13) 62.38 (3H, s,

CH3), 2.69-2.78 (2H, m, ArCH2CH2), 2.96-3.06 (2H, m, ArCH2), 7.26 (lH, s, ArH); I 3 c

NMR (CDC13) 6 17.6, 21.8, 34.8, 128.4, 148.6, 149.31, 153.0, 153.5, 203.7; IR (KBr)

1714, 1587, 1439, 1421, 1285, 1256, 1203, 1112, 871, 570 cm-'; MS (CI) m/z (rel.

intensity) 182 (M + H, 100); Anal. Calcd. for C9H8ClNO: C, 59.52; H, 4.44; N, 7.71.

Found: C, 59.44; H, 4.44; N, 7.67.

To a stirred solution of the chloroketone 269 (101 mg, 0.550 mmol) in benzene (3

mL) was added (2R,3R)-2,3-butanediol 270a (76 pL, 0.83 mmol) and para-

toluenesulfonic acid monohydrate (16 mg, 83 pmol) and the resultant solution was heated

at reflux in a Dean-Stark apparatus for 16 h. The reaction mixture was then allowed to

cool to room temperature and potassium carbonate (100 mg) was added. After an

additional 10 min, the reaction mixture was filtered and the filter-cake was washed with

ether (10 mL). The combined filtrates were concentrated in vacuo to afford the crude

product. Flash chromatography using hexanes:ether (2: 1) as the eluant afforded the title

compound 268a (119 mg, 85%) as a white crystalline solid. M.p. 84-86 "C,

hexaneslether; [a] 2 - 24.7 (c 1.15, chloroform); 'H NMR (C6D6) 6 1.14 (3H, d, J = 6.1

Hz, CHCH3), 1.38 (3H, d, J = 6.1 Hz, CHCH3), 1.47 (3H, s, CH3), 2.19-2.25 (2H, m,

ArCH2CH2), 2.37-2.43 (2H, m, ArCH2), 3.73 (lH, dq, J = 6.1, 8.2 Hz, OCH), 4.68 (IH,

dq, J=6 .1 , 8.2 HZ, OCH), 6.61 (lH, S, ArH); 13c NMR (C6D6) 617.1, 17.9, 18.1, 24.1,

36.7, 79.8, 80.5, 114.6, 124.9, 134.8, 147.4, 151.7, 163.6; IR (KBr) 2980, 2935, 2978,

1594, 1457, 1443, 1377, 1316, 1296, 1264, 1228, 1204, 1183, 1161, 1130, 1112, 1085,

1048, 978, 938, 899, 873, 865, 833 cm-'; MS (CI) m/z (rel. intensity) 254 (M + H, loo),

182 (33); Anal. Calcd. for C13H16C1N02: C, 61.54; H, 6.36; N, 5.52. Found: C, 61.48; H,

To a stirred solution of the chloroketone 269 (25 1 mg, 1.38 mmol) in benzene (8

mL) was added (lS,2S)- l,2-diisopropyl- l,2-ethanediol 270b115 (22 1 mg, 1.52 mmol) and

para-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) and the resultant solution

was heated at reflux in a Dean-Stark apparatus for 16 h. The reaction mixture was then

allowed cool to room temperature and potassium carbonate (100 mg) was added. After

an additional 10 min, the reaction mixture was filtered and the filter-cake was washed

with ether (25 mL). The combined filtrates were concentrated in vacuo to afford the

crude product. Flash chromatography using hexanes:ether (4: 1) as the eluant afforded the

title compound 268b (380 mg, 89%) as a colourless oil that crystallized upon standing.

M.p. 34-35 OC; [a] - 30.8 (c 1.10, chloroform); 'H NMR (CDC13) 6 0.93 (3H, d, J =

6.9 Hz, CHCH3), 0.95 (3H, d, J = 6.5 Hz, CHCH3), 0.99 (3H, d, J = 6.9 Hz, CHCH3),

1.0 1 (3H, d, J = 6.5 Hz, CHCH3), 1.77- 1.87 (1 H, m, CH(CH3)2), 2.16-2.28 (4H, m, CH3

and CH(CH3)2), 2.33-2.38 (2H, m, ArCH2CH2), 2.71-2.78 (2H, m, ArCH2), 3.63 (IH, dd,

J = 5.5, 7.6Hz, OCH),4.11 (lH, apparent t, J = 5.8 Hz, OCH), 7.02 (lH, s, ArH); 13c

NMR (CDC13) 6 17.6, 18.4, 19.0, 19.7, 20.2, 24.0, 31.5, 31.7, 37.1, 86.0, 86.1, 114.8,

124.8, 135.1, 147.3, 151.3, 161.7; IR (KBr) 2961, 1594, 1442, 1384, 1318, 1299, 1202,

1 170, 1056, 922, 865, 63 1 cm-'; MS (CI) m/z (rel. intensity) 3 10 (M + H, 1 OO), 182 (20);

Anal. Calcd. for C17H24ClN02: C, 65.90; H, 7.81; N, 4.52. Found: C, 65.72; H, 7.85; N,

To a stirred solution of the chloroketone 269 (100 mg, 0.55 1 mmol) in benzene (3

mL) was added (1S,2S)- 1,2-diphenyl- l,2-ethanediol 270c (1 52 mg, 0.709 mmol) and

para-toluenesulfonic acid monohydrate (16 mg, 0.083 mmol) and the resultant solution

was heated at reflux in a Dean-Stark apparatus for 16 h. The reaction mixture was then

allowed cool to room temperature and potassium carbonate (100 mg) was added. After

an additional 10 min, the reaction mixture was filtered and the filter-cake was washed

with ether (10 mL). The combined filtrates were concentrated in vacuo to afford the


title compound 26% (163 mg, 79%) as a colourless oil that crystallized upon standing.

M.p. 44-46 "C, hexaneslether; [a]: - 108 (c 0.38, chloroform); 'H NMR (C6D6) 6 1.54

(3H, s, CH3), 2.26-2.32 (2H, m, ArCH2CH2), 2.5 1-2.65 (2H, m, ArCH2), 4.99 (1 H, d, J =

8.9 Hz, OCH), 5.99 (lH, d, J = 8.9 Hz, OCH), 6.68 (IH, s, ArH), 7.07-7.15 (4H, m,

ArH), 7.18-7.29 (4H, m, AH), 7.74-7.79 (2H, m, ArH); 13c NMR (C6D6) G 17.4, 23.5,

36.3, 86.5, 87.2, 115.0, 124.8, 127.2, 128.5, 128.6, 130.5, 131.9, 134.8, 136.9, 137.4,

143.0, 147.1, 151.4, 162.3; IR (KBr) 2914, 2362, 2336, 1594, 1570, 1496, 1453, 1443,

1384, 1320, 1298, 1267, 1229, 1201, 1160, 11 13, 1059, 1021, 939, 925, 879, 759, 699

cm-'; MS (CI) m/z (rel. intensity) 378 (M + H, 41), 271 (27), 182 (100); Anal. Calcd. for

C23H20CIN02: C, 73.1 1; H, 5.33; N, 3.71. Found: C, 72.96; H, 5.39; N, 3.78.

8.2.9. Preparation of 4,4'-Dimethyl-6,6 ', 7,7'-tetrahydro-SH, 5 'H-2,2 '-bi([l]pyrindinyl)-

7,7'-dione (2R,3R)-2,3-Butanediol bis-Acetal (267a) and 4-Methyl-6,7-dihydro-5H-

[l]pyrindin-7-one (2R,3R)-2,3-Butanediol Acetal (286) from the 2-Chloropyridine

(268a)

Me\ Me Me\

To a stirred solution of dibromobis(triphenylphosphine)nicke1(11) (1.17 g, 1.58

mmol) in degassed tetrahydrofuran (30 mL) were added zinc dust ( 4 0 microns, 3 10 mg,

4.74 mmol) and tetraethylammonium iodide (812 mg, 3.16 mmol). The reaction mixture

was stirred at room temperature for 30 min and then a solution of the 2-chloropyridine

268a (800 mg, 3.16 mmol) in degassed tetrahydrofuran (12 mL) was added via a cannula.

The resultant mixture was heated at 60 OC for 72 h and then allowed to cool to room

temperature. The reaction mixture was poured into an aqueous solution of ammonium

hydroxide (10% wlw, 200 mL) and was extracted with a mixture of ether and benzene

(1:1, 3 x 100 mL). The combined organic extracts were washed with water (2 x 20 mL),

dned over anhydrous sodium sulfate and concentrated in vacuo to afford the crude

product. Flash chromatography using chloroform as the eluant afforded the title

compound 267a (242 mg, 35%) as white crystalline solid and the title compound 286

(269 mg, 39%) as a white crystalline solid. Title compound 286: M.p. 52-54 "C,

chloroform; [a] 2 - 14.9 (c 1.02, chloroform); 'H NMR (CDC13) S 1.33 (3H, d, J = 6.1

Hz, CH3), 1.41 (3H, d, J = 6.1 Hz, CH3), 2.25 (3H, s, ArCH3), 2.35-2.41 (2H, m,

ArCH2CH2), 2.79-2.86 (2H, m, ArCH2), 3.77 (lH, dq, J = 6.1, 7.8 Hz, CHCH3), 4.32

(lH, dq, J = 6.1, 8.0 Hz, CHCH3), 7.00 (lH, d, J = 4.9 Hz, ArH), 8.40 (lH, d, J = 4.9 Hz,

ArH); 13c NMR (CDC13) S 16.7, 16.8, 18.2, 24.3, 36.2, 79.4, 114.1, 124.7, 135.9, 144.4,

149.4, 161.0; IR (KBr) 2974, 2921, 2862, 1602, 1448, 1378, 1331, 1303, 1192, 1162,

1094, 926 cm-'; MS (CI) rn/z (rel. intensity) 220 (M + H, loo), 148 (8); Anal. Calcd. for

C13H17N02: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.07; H, 7.84; N, 6.32. Title

compound 267a: M.p. 292-294 "C, chloroform; [a] 20 - 53.7 (c 0.99, chloroform); 'H

NMR (CDC13) S 1.35 (6H, d, J = 6.1 HZ, CHCH3), 1.57 (6H, d, J = 6.0 HZ, CHCH3),

2.33 (6H, s, ArCH3), 2.41-2.49 (4H, m, ArCH2CH2), 2.83-2.89 (4H, m, ArCH2), 3.84

(2H, dq, J = 6.0, 8.0 Hz, CHCH3), 4.55 (2H, dq, J = 6.0, 7.8 Hz, CHCH3), 8.2 1 (2H, s,

ArH); 13c NMR (CDC13) S 16.8, 17.6, 18.6, 24.3, 36.1, 79.0, 79.6, 114.4, 122.1, 135.5,

144.5, 156.5, 160.8; IR (KBr) 2982, 2970, 2935, 2896, 1591, 1432, 1423, 1379, 1321,

1293, 1204, 1 18 1, 1 162, 1095, 1076, 1059 cm-'; MS (CI) m/z (rel. intensity) 437 (M + H,

loo), 365 (45), 167 (48); Anal. Calcd. for C26H32N204: C, 71.53; H, 7.39; N, 6.42.

Found: C, 71.38; H, 7.22; N, 6.26.

CPr CP? CPr

To a stirred solution of dibromobis(triphenylphosphine)nickel(II) (609 mg, 0.82

mmol) in degassed tetrahydrofuran (12 mL) were added zinc dust (<lo microns, 162 mg,

2.48 mmol) and tetraethylammonium iodide (424 mg, 1.65 mmol). The reaction mixture


268b (5 11 mg, 1.65 mmol) in degassed tetrahydrofuran (6 mL) was added via a cannula.

The resultant mixture was heated at 60 OC for 72 h and then was allowed to cool to room

temperature. The reaction mixture was poured into an aqueous solution of ammonium

hydroxide (10% wlw, 200 mL) and was extracted with ether (3 x 50 mL). The combined

organic extracts were washed with water (2 x 20 mL), dried over anhydrous sodium

sulfate and concentrated in vacuo to afford the crude product. Flash chromatography

using hexanes:ether (10: 1) as the eluant afforded the title compound 267b (326 mg, 72%)

as a white crystalline solid. M.p. 166-167 OC, hexaneslether; [a] - 44.3 (c 0.37,

chloroform); 'H NMR (CDC13) 6 0.99-1.08 (24H, m, CHCH3), 1.82-1.95 (2H, m,

CHCH3), 2.31 (6H, s, ArCH3), 2.39-2.45 (4H, m, ArCH2CH2), 2.46-2.58 (2H, m,

CHCH3), 2.8 1-2.87 (4H, m, ArCH2), 3.72 (2H, dd, J = 4.8, 7.8 Hz, OCH), 4.18 (2H, dd,

J = 4.8, 6.4 Hz, OCH), 8.21 (2H, s, ArH); 13c NMR (CDC13) 6 17.8, 18.6, 19.0, 19.4,

19.9, 24.2, 31.5, 31.8, 37.1, 85.8, 86.1, 115.5, 122.2, 135.9, 144.4, 156.5, 160.3; IR

1 148, 1099, 1056, 1009, 921 cm-'; MS (MALDI-TOF) m/z 550 (M + H); Anal. Calcd.

for C34H4*N204: C, 74.42; H, 8.82; N, 5.10. Found: C, 74.60; H, 8.95; N, 5.30.

To a stirred solution of dibromobis(triphenylphosphine)nickel(II) (743 mg, 1 .OO

mmol) in degassed tetrahydrofuran (15 mL) were added zinc dust ( 4 0 microns, 197 mg,

3.02 mmol) and tetraethylammonium iodide (5 17 mg, 2.0 1 mmol). The reaction mixture


268c (760 mg, 2.01 mmol) in degassed tetrahydrofuran (12 mL) was then added via a

cannula. The resultant mixture was heated at 60 OC for 72 h and then was allowed to cool

to room temperature. The reaction was then poured into an aqueous solution of

ammonium hydroxide (10% wlw, 300 mL) and was extracted with ether (3 x 50 mL).

The combined organic extracts were washed with water (2 x 20 mL), dried over

anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Flash

chromatography using hexanes:ether (6: 1) as the eluant afforded the title compound 267c

(502 mg, 73%) as a white crystalline solid. M.p. 214-215 OC, hexaneslether; [a] + 250

(c 1.00, chloroform); 'H NMR (CDC13) 6 2.39 (6H, s, ArCH3), 2.70-2.84 (4H, my

ArCH2CH2), 2.97-3.07 (4H, m, ArCH2), 4.95 (2H, d, J = 8.5 Hz, CH), 5.79 (2H, d, J =

8.5 Hz, CH), 7.28-7.45 (16H, m, ArH), 7.65-7.78 (4H, m, ArH), 8.39 (2H, s, ArH); 13c

NMR (CDC13) 6 18.7, 24.3, 36.1, 86.0, 86.5, 115.7, 122.5, 127.0, 128.0, 128.4, 128.5,

136.0, 136.6, 137.8, 145.0, 156.7, 161.0; IR (KBr) 2366, 2341, 1594, 1498, 1436, 1422,

1326, 1195, 1159, 1141, 1099, 1023, 938, 916, 761, 700 cm-'; MS (MALDI-TOF) m/z

686 (M + H); Anal. Calcd. for C46H40N204: C, 80.68; H, 5.89; N, 4.09. Found: C, 80.50;

H, 5.77; N, 4.06.

A solution of the 2-hydroxypyridine 280 (3.00 g, 20.1 mmol) in phosphorus

tribromide (4.5 mL, 47 mmol) was heated at reflux for 12 h. The reaction mixture was

then allowed to cool to room temperature and was poured into an ice-cold aqueous

solution of sodium hydroxide (2 M, 300 mL). The resultant mixture was extracted

(gentle agitation to avoid emulsification) with ethyl acetate (3 x 200 mL). The combined

organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to

afford the crude product. Flash chromatography using chloroform as the eluant afforded

the title compound 287 (2.20 g, 52%) as a colourless oil which crystallized upon

standing. M.p. 35-36 OC; 'H NMR (CDC13) 62.04-2.16 (2H, m, ArCH2CH2), 2.21 (3H,

s, CH3), 2.80 (2H, apparent t, J = 7.5 Hz, ArCH2), 2.99 (2H, apparent t, J = 7.8 Hz,

ArCH2), 7.05 (lH, s, ArH); 13c NMR (CDC13) 6 18.7, 25.9, 32.31, 74.9, 127.7, 135.3,

141.1, 147.4, 165.2; IR (KBr) 2356, 2337, 1733, 1717, 1700, 1684, 1653, 1558, 1507,

1458, 1419, 1375, 1305, 1261, 1186, 1090, 865 cm-'; MS (CI) m/z (rel. intensity) 213

[M("B~) + H, 971, 21 1 [ M ( ~ ~ B ~ ) + H, 1001; Anal. Calcd. for C9HloNBr: C, 50.97; H,

4.75; N, 6.60. Found: C, 50.66; H, 4.73; N, 6.39.

To a stirred solution of the 2-bromopyridine 280 (2.20 g, 10.4 mmol) in glacial


mL, 49 mmol). The resultant solution was heated at 80 OC for 20 h and then was allowed

to cool to room temperature. The reaction mixture was concentrated in vacuo and the

residue was taken up in water (100 mL). The resultant slightly acidic mixture was

neutralized by the careful addition of solid potassium carbonate which was then extracted

with chloroform (3 x 50 mL). The combined organic extracts were dried over anhydrous

sodium sulfate and concentrated in vacuo to afford the pyridine N-oxide (2.35 g, 99%) as

a white crystalline solid. This material was taken up in acetic anhydride (20 mL) and the

resultant mixture was heated slowly to 100 OC over 2 h. The resultant solution was

heated at 100 OC for 2 h and then was allowed to cool to room temperature. The reaction

mixture was then concentrated in vacuo and purified by flash chromatography using

hexanes:ether (1: 1) as the eluant to afford the title compound 288 (1.50 g, 54%, over two

steps) as a light orange oil which crystallized upon standing. M.p. 68-69 OC; 'H NMR

(CDC13) S 2.00-2.1 1 (4H, m, ArCH2CHH and CH3CO), 2.26 (3H, s, ArCH3), 2.68-2.68

(lH, m, ArCH2CHH), 2.69-2.80 (lH, m, ArCHH), 2.87-2.98 (lH, m, ArCHH), 5.98-6.02

(lH, m, CHOAc), 7.22 (lH, s, ArH); 13c NMR (CDC13) S 18.7, 21.5, 26.3, 30.6, 62.5,

122.9, 136.9, 141.5, 147.2, 160.8, 170.8; IR (KBr) 2363, 2337, 1734, 1653, 1635, 1559,

1541, 1507, 1370, 1337, 1235, 1094, 1036, 856 cm-'; MS (CI) m/z (rel. intensity) 272

[M("B~) + H, 971, 270 [M(I9Br) + H, 1001, 212 (30), 101 (35); Anal. Calcd. for

CllH12N02Br: C, 48.91; H, 4.48; N, 5.19. Found: C, 48.63; H, 4.43; N, 5.32.

A stirred solution of the acetate 288 (1.50 g, 5.55 mmol) and lithium hydroxide

monohydrate (932 mg, 22.2 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was

stirred at room temperature for 5 h. The reaction mixture was then diluted with water (25

mL) and extracted with chloroform (3 x 25 mL). The combined organic extracts were

dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude

product. Flash chromatography using hexanes:ether (1 : 1) as the eluant afforded the title

compound 289 (1.20 g, 95%) as a white crystalline solid. M.p. 110-111 OC,

hexaneslether; 'H NMR (CDC13) 61.99-2.12 (lH, m, ArCH2CHH), 2.26 (3H, s, ArCH3),

2.48-2.59 (lH, m, ArCH2CHH), 2.63-2.75 (lH, m, ArCHH), 2.87-2.97 (lH, m, ArCHH),

5.18 (lH, apparent t, J = 7.2 Hz, CHOH), 7.19 (lH, s, ArH); 13c NMR (CDC13) 6 18.6,

25.8, 32.2, 74.8, 127.6, 135.2, 141.0, 147.3, 165.1; IR (KBr) 3258, 2361, 1733, 1717,

1700, 1684, 1653, 1636, 1559, 1541, 1507, 1187, 1090, 863 cm-'; MS (CI) m/z (rel.

intensity) 230 [ ~ ( ' l ~ r ) + H, 221, 228 [ M ( ~ ~ B ~ ) + H, 221, 201 (loo), 173 (25), 118 (18),

91 (53), 77 (36), 65 (36), 5 1 (33), 39 (42); Anal. Calcd. for C9HloNOBr: C, 47.39; H,

4.42;N7 6.14. Found: C, 47.61;H74.45;N, 5.98.

To a stirred solution of oxalyl chloride (4 15 pL, 4.76 mmo) in dichloromethane

(40 mL) at -78 "C was added dimethylsulfoxide (1.10 mL, 14.2 mmol) dropwise over -5

min. The resultant solution was stirred for 10 min and then a solution of the alcohol 289

(900 mg, 3.95 mmol) in anhydrous dichloromethane (15 mL) was added via a cannula.

After an additional 10 min, triethylamine (2.80 mL, 20.1 mmol) was added and the

reaction mixture was then allowed to warm to room temperature. The resultant mixture

was then diluted with additional dichloromethane (50 ml) and washed with water (50

mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude

product. Flash chromatography using dichloromethane as the eluant afforded the

bromoketone 290 (804 mg, 90%) as a white crystalline solid M.p. 188-189 "C,

dichloromethane; 'H NMR (CDC13) 62.39 (3H, s, CH3), 2.74-2.80 (2H, m, ArCH2CH2),

2.97-3.02 (2H, m, ArCH2), 7.46 (lH, s, ArH); 13c NMR (CDC13) 6 17.5, 2 1.9, 34.7,

152 1, 1094 cm-'; MS (CI) m/z (rel. intensity) 228 [ ~ ( ~ l ~ r ) + H, 1001, 226 [ M ( ~ ~ B ~ ) + H,

1001; Anal. Calcd. for C9H8NOBr: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.71; H, 3.48;

To a stirred solution of the bromoketone 290 (650 mg, 2.87 mmol) in benzene (15

mL) was added (2R,3R)-2,3-butanediol 270a (0.33 mL, 3.6 mmol) and p-toluenesulfonic

acid monohydrate (82 mg, 0.43 mmol) and the resultant solution was heated at reflux in a

Dean-Stark apparatus for 20 h. The reaction mixture was then allowed to cool to room

temperature and potassium carbonate (200 mg) was added. After an additional 10 min,

the reaction mixture was filtered and the filter-cake was washed with ether (15 mL). The

combined filtrates were concentrated in vacuo to afford the crude product. Flash

chromatography using hexanes:ethyl acetate (2:l) as the eluant afforded the title

compound 291a (760 mg, 89%) as a white crystalline solid M.p. 128-129 "C,

hexaneslethyl acetate; [a] - 25.8 (c 1 .O7, chloroform); 'H NMR (CDC13) S 1.3 1 (3H, d,

J = 6.1 Hz, CHCH3), 1.41 (3H, d, J = 6.1 Hz, CHCH3), 2.22 (3H, s, ArCH3), 2.35-2.40

(2H, m, ArCH2CH2), 2.72-2.78 (2H, m, ArCH2), 3.72-3.90 (lH, m, CHCH3), 4.35-4.43

(IH, m, CHCH3), 7.19 (lH, s, ArH); 13c NMR (CDCI3) S 16.6, 17.1, 18.1, 23.9, 35.9,

79.2, 79.7, 113.6, 128.4, 135.0, 141.8, 147.1, 162.4; IR (KBr) 2985, 2933, 2361, 2331,

1588, 1441, 1376, 1314, 1263, 1204, 1107, 1077, 931, 865 cm-'; MS (CI) m/z (rel.

intensity) 300 [M("B~) + H, 971, 298 [ M ( ~ ~ B ~ ) + H, 1001, 226 (21), 1 15 (53); Anal.

Calcd. for CI3Hl6NO2Br: C, 52.36; H, 5.41; N, 4.70. Found: C, 52.25; H, 5.47; N, 4.61.

8.2.17. Preparation of 4,4 '-Dimethyl-6,6 ', 7,7'-tetrahydro-5H,5 'H-2,2 '-

bi((lJpyrindiny1)- 7,7'-dione (2R,3R)-Butanediol bis-Acetal(267a) from the 2-

Bromopyridine (291a)

To a stirred solution of dibromobis(triphenylphosphine)nickel(II) (224 mg, 0.302

mmol) in degassed tetrahydrofuran (15 mL) were added zinc dust (<lo microns, 197 mg,

3.02 mmol) and tetraethylammonium iodide (517 mg, 2.01 mmol) and the resulting

mixture was stirred at room temperature for 30 min. A solution of the 2-bromopyridine

291a (600 mg, 2.01 mmol) in degassed tetrahydrofuran (6 mL) was then added via a

cannula and the resultant mixture was heated at 60 OC for 72 h. The reaction mixture was

then allowed to cool to room temperature and was poured into an aqueous solution of

ammonium hydroxide (10% wlw, 150 mL). The resultant mixture was extracted with a

mixture of ether and benzene (1:1, 3 x 100 mL). The combined organic extracts were

washed with water (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in

vacuo to afford the crude product. Flash chromatography using chloroform as the eluant

afforded the title compound 267a (364 mg, 83%) as a white crystalline solid. The

spectroscopic data were in agreement with that recorded above.

8.2.1 8. 4-Methyl-2-(2 '-pyridyl+6,7-dihydro-SH-[lJpyrindin- 7-one (2R,3R)-2,3-

Butanediol Acetal(271a)

To a stirred solution the 2-chloropyridine 268a (175 mg, 0.690 mmol) and 2-(tri-

n-butylstanny1)pyridine 272 (472 mg, 0.759 mmol) in anhydrous, degassed dioxane (3

mL) at room temperature were added tris(dibenzylideneacetone)dipalladium(0) (16 mg,

17 pmol), a solution of tri-tert-butylphosphine in tetrahydrofuran (0.10 M, 0.69 mL, 69

pmol) and anhydrous cesium fluoride (23 1 mg, 1.52 mmol). The resultant solution was

heated at reflux for 24 h and then was allowed to cool to room temperature. The reaction

mixture was filtered through a pad of silica gel using ethyl acetate as the eluant and the

filtrate was then concentrated in vacuo to afford the crude product. Flash

chromatography using hexanes:ether (4: 1) as the eluant afforded the title compound 271a

(147 mg, 72%) as a white crystalline solid. M.p. 164-165 "C, hexaneslether; [a] - 40.8

(c 1.04, chloroform); 'H NMR (CDC13) 6 1.37 (3H, d, J = 6.1 Hz, CHCH3), 1.52 (3H, d,

J = 6.0 Hz, CHCH3), 2.34 (3H, s, ArCH3), 2.44-2.50 (2H, m, ArCH2CH2), 2.85-2.91 (2H,

m, ArCH2), 3.80-3.89 (lH, m, CHCH3), 4.54-4.62 (IH, m, CHCH3), 7.25-7.29 (IH, m,

ArH), 7.76-7.84 (lH, my ArH), 8.20 (IH, s, ArH), 8.45-8.49 (IH, my ArH), 8.63-8.67

(lH, m, ArH); 13c NMR (CDC13) 6 16.7, 17.6, 18.4, 24.3, 36.0, 79.1, 79.7, 114.3, 121.3,

122.0, 123.5, 136.0, 136.9, 145.1, 148.9, 155.8, 156.7, 161.3; IR (KBr) 1586, 1565,

1441, 1376, 13 16, 1 191, 1096, 1079, 932, 896, 798 cm-'; MS (CI) m/z (rel. intensity) 297

(M + H, 100); Anal. Calcd. for C18H20N202: C, 72.95; H, 6.80; N, 9.45. Found: C, 72.68;

H, 7.00; N, 9.17.

To a stirred solution the 2-chloropyridine 268c (261 mg, 0.690 mmol) and 2-(tri-

n-butylstanny1)pyridine 272 (472 mg, 0.759 mmol) in anhydrous, degassed dioxane (5

mL) at room temperature were added tris(dibenzylideneacetone)dipalladium(0) (16 mg,

17 pmol), a solution of tri-tert-butylphosphine in tetrahydrofuran (0.10 M, 0.69 mL, 69

pmol) and anhydrous cesium fluoride (23 1 mg, 1.52 mmol). The resultant solution was

heated at reflux for 24 h and then was allowed to cool to room temperature. The reaction

mixture was filtered through a pad of silica gel using ethyl acetate as the eluant and the

filtrate was then concentrated in vacuo to afford the crude product. Flash

chromatography using hexanes:ether (4: 1) as the eluant afforded the title compound 271b

(242 mg, 83%) as a white crystalline solid. M.p. 120-121 "C, hexanedether; [a] - 98.4

1 (c 1.00, chloroform); H NMR (CDCl,) 6 2.40 (3H, s, CH3), 2.68-2.82 (2H, m,

ArCHCH*), 2.96-3.03 (2H, m, ArCHz), 4.92 (lH, d, J = 8.5 Hz, CH), 5.77 (lH, d, J =

8.5 Hz, CH), 7.29-7.37 (9H, m, ArH), 7.61-7.66 (2H, m, Arm, 7.80-7.86 (lH, m, ArH),

8.30 (lH, s, ArH), 8.52-8.56 (lH, m, ArH), 8.67-8.71 (lH, m, Arm; 13c NMR (CDC13) 6

18.5, 24.3, 36.1, 86.1, 86.5, 115.6, 121.4, 122.2, 123.6, 126.9, 127.9, 128.4, 128.5, 128.5,

700 cm-l; MS (CI) m/z (rel. intensity) 42 1 (M + H, 90), 3 14 (2), 225 (100); Anal. Calcd.

for C28H24N202: C, 79.98; H, 5.75; N, 6.66. Found: C, 79.64; H, 6.02; N, 6.30.

8.2.20. General Procedure for the Copper(l)-Catalyzed Enantioselective

Cyclopropanation of Styrene (292) with the Ethyl and tert-Butyl Esters of Diazoacetic

Acid (293a,b)

1.25 mol % CU(OT~)~, 1.3 - 2.6 mol % L* 267a-c or 271a,b,

1.5 mol % PhNHNH2, C02R C02R CH2CI2, room temperature, 15 h

phF + L

N2 - P

Ph

292 293a,b 294a, b

To a stirred solution of copper(I1) triflate (9.0 mg, 25 pmol) in dichloromethane (4

mL) was added the 2,2'-bipyridyl ligand 267a-c or the unsymmetrical bipyridyl ligand

271a,b (30 pmol or 55 pmol) and the resultant solution was stirred at room temperature

for 30 min. Phenylhydrazine (3.0 pL, 30 pmol) and styrene 292 (0.50 mL, 4.4 mmol)

were then added. A solution of the ethyl or tert-butyl ester of diazoacetic acid 293a,b

(2.00 mmol) in dichloromethane (3 mL) was then added over -3 h via syringe pump.

After the addition was complete, the reaction mixture was stirred for an additional 12 h.

The resultant mixture was concentrated in vacuo to afford the crude product. The ratios

of the trans- and cis-isomers of the cyclopropane reaction products were then determined

by 'H NMR spectroscopy. Flash chromatography using petroleum ether:ethyl acetate

(96:4) as the eluant afforded the pure trans-cyclopropanes 294a,b and the corresponding

cis-cyclopropanes. The enantiomeric purities of the major trans-isomers of the

cyclopropane reaction products were determined following reduction with lithium

aluminum hydride.

8.2.21. trans-2-Phenyl-cyclopropane-1-carboxyl Acid Ethyl Ester (294a)

C02Et

'H NMR (CDC13) 6 1.25-1.34 (4H, m, CH3 and CHH), 1.56-1.63 (lH, m, CHH), 1.87-

1.93 (lH, m, CHC02Et), 2.52 (lH, ddd, J = 10.2, 6.4,4.1 Hz, CHPh), 4.17 (2H, q, J = 7.2

Hz, CH2CH3), 7.07-7.14 (2H, m, ArH), 7.17-7.23 (lH, m, ArH), 7.24-7.32 (2H, m, ArH);

13c NMR (CDC13) 614.4, 17.2, 24.3, 26.3, 60.8, 126.3, 126.6, 128.6, 140.3, 173.5; IR

(neat) 2988, 1721, 1603, 1496, 1411, 1189, 1040, 1019, 847, 761, 722, 701 cm-'; MS

(CI) m/z (rel. intensity) 191 (M + H, 100). Analytical chiral HPLC analysis of the

corresponding primary alcohol using a Daicel Chiracel OD column [hexanes:isopropanol

(90:10), flow rate at 0.5 mL/min, detection at A = 220 nm, tl = 15.4 min, t2 = 25.2 min].

8.2.22. trans-2-Phenyl-cyclopropane-1-carboxylic Acid tert-Butyl Ester (294b)

'H NMR (CDCl,) 6 1.23 (lH, m, CHH), 1.47 (9H, s, t-Bu), 1.50-1.56 (lH, m, CHH),

1.84 (lH, m, CHC02t-Bu), 2.44 (1 H, m, CHPh), 7.06-7.12 (2H, m, ArH), 7.16-7.22 (1 H,

m, ArH), 7.24-7.3 1 (2H, m, ArH); 13c NMR (CDC13) 6 17.4, 25.6, 26.1, 28.5, 80.9,

126.4, 126.7, 128.7, 140.9, 172.9; IR (neat) 2977, 1715, 1606, 1498, 1403, 1367, 1343,

1222, 1152, 936, 844, 783, 761, 744 cm-'; MS (CI) m/z (rel. intensity) 219 (M + H, 18),

163 (1 00). Analytical chiral HPLC analysis of the corresponding primary alcohol using a

Daicel Chiracel OD column [hexanes:isopropanol (90:10), flow rate at 0.5 mLImin,

detection at A = 220 nm, tl = 15.4 min, t2 = 25.2 min].

8.2.23. Procedure for the Preparation and Crystallization of bis-[4,4'-Dimethyl-

6,6 ', 7,7'-tetrahydro-SH,S'H-2,2'-bi([lJpyrindinyI)- 7,7 '-dione (1S,2S)-1,2-Diphenyl-1,2-

ethanediol bis-Acetal/ (267c) Copper(1) Chloride Complex

A solution of the ligand 267c (35 mg, 5 1 pmol) and copper(1) chloride (5.0 mg, 5 1

pmol) in a mixture of ethano1:dichloromethane (1:1, 3 mL) was stirred at room

temperature for 4 h. The reaction mixture was then concentrated in vacuo to afford the

crude product. This material was then taken up in dichloromethane (2 mL) and was

filtered through a plug of glass wool. Ether (3 mL) was then added to the filtrate and

upon slow evaporation, the title compound (27 mg, 68%) was obtained as X-ray quality

red crystals. M.p. >220 "C (dec.), etherldichloromethane; [a] f:, - 2500, [a] i:, - 4900,

[a] :", - 3400, [a] ::, - 1333, [a] ::, - 1300 (c 0.0030, chloroform); UV-Vis A,,,

(chloroform) 287 (E = 38158), 309 (E = 38684), 472 (E = 6158) nm; IR (KBr) 1603, 1496,

1315, 1167, 1140, 1056, 1023, 951, 807, 759 cm-'; MS (MALDI-TOF) m/z 1431 (M -

CuC12), 747 (M - CuC12 - L); Anal. Calcd. for C92H80C12C~2N408: C, 70.49; H, 5.14; N,

3.57. Found: C,70.36;H,5.15;N,4.10.

8.2.24. X-Ray Crystallographic Analysis of the Cu(267c)~-CuCI2 Complex

A single crystal, a red block that had the dimensions 0.17 x 0.40 x 0.94 mm3, was

mounted on a glass fiber using epoxy adhesive. The data for this crystal of the

Cu(267~)~.CuC12 complex was acquired at 293 K on a Rigaku M S - R A P I D curved

image plate area detector with graphite monochromated Cu KQ radiation. Indexing for

the crystal was performed using four, 5 " oscillations that were exposed for 300 seconds.

The following data range was recorded: 4.65" 5 219 5 144.25" and a total of fifty four

images were collected. A sweep of data was then collected using w scans from 0.0" to

180.0" in 10" steps, at z= 0.0" and += 0.0". A second sweep of data was collected using

w scans from 0.0" to 180.0" in 10" steps, at z= 45.0" and += 0.0". A final sweep of data

was collected using w scans from 0.0" to 180.0" in 10" steps, at z = 45.0" and + = 90.0".

The exposure rate was 75 secI0 and in each case, the crystal-to-detector distance was

127.40 mm. A numerical absorption correction was then applied which resulted in the

following transmission range: 0.4114 to 0 .6854. '~~ The coordinates and anisotropic

displacement parameters for the non-hydrogen atoms were then refined with the

exception of C1(5), Cl(6) and C(47). Of note, hydrogen atoms were placed in calculated

positions (d C-H 0.95 A) and their coordinate shifts were linked with those of the

respective carbon atoms during refinement. Isotropic thermal parameters for the

hydrogen atoms were initially assigned proportionately to the equivalent isotropic

thermal parameters of their respective carbon atoms. Subsequently, the isotropic thermal

parameters for the hydrogen atoms were constrained to have identical shifts during

(176) de Meulenaer, J.; Tompa, H. Absorption Correction in Crystal Structure Analysis. Acta Ctyst. 1965,

19. 1014.

refinement. The programs used for all absorption corrections, data reduction, and

processing were from the Rigaku CrystalClear package. The structure was refined using

CRYSTALS.'~~ Complex scattering factors for neutral atoms were used in the calculation

of structure f a ~ t 0 r s . l ~ ~ An ORTEP representation of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex is

provided below (Figure 8.2.1. and 8.2.2.). Crystallographic data, fractional atomic

coordinates and equivalent isotropic thermal displacement parameters, selected bond

lengths, and selected bond angles for the C~(267c)~*CuCl~ complex are also listed below

(Table 8.2.1 ., 8.2.2., 8.2.3. and 8.3.4., respectively).

(177) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.; Cooper, R. I. CRYSTALS Issue 12.50;

Chemical Crystallography Laboratory, University of Oxford, Oxford, 2003.

(178) International Union of Crystallography. International Tables for X-Ray Crystallography; Kynoch

Press: Birmingham, 1952.

Figure 8.2.1. ORTEP representation of the C ~ ( 2 6 7 c ) ~ C u C l ~ complex.'

(*) The thermal ellipsoids are drawn at a 25% probability level and the hydrogen atoms as wcll as the

atoms of the incorporated solvent molecule (CH2CIZ) have been removed for clarity. Symmetry

transformations: ( * ) - x - 2 , - y - l , z ; ( ' ) - x - 3 , - y - 1,z.

Figure 8.2.2. Partial ORTEP representation of the C ~ ( 2 6 7 c ) ~ C u C I ~ complex showing the carbon

atom numbering scheme of the 2,2'-bipyridyl ligand.

Table 8.2.1. Summary of Crystallographic Data for the C~(267c)~-CuCI~ Complex

Empirical formula C93H82C14C~2N408

F W (g mol-') 1648.35

Temperature (K)

Wavelength (Cu K a , A)

Crystal system

Space group

293

1.541 80

Orthorhombic

P21212

a (A) 14.7325(4)

b (A) 15.2366(2)

c (A) 19.0213(3)

a ("1 90

P (") 90

Y ("> 90

z 2

u (A3) 4269.77(15)

Dcalc (g crf3) 1.285

20 limits (") 4.65-144.25

Reflections collected 28285

Independent reflections 6828

Reflections observed [I = 2.5o(0] 4566

Goodness-of-fit on F 0.60 1

R i 7 Rw [ I= 2.5401 0.0532,0.750

Table 8.2.2. Fractional Atomic Coordinates (A) and Equivalent Isotropic Thermal Displacement

Parameters [U(iso), (A2)] for the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex *

atom x Y z U (iso)

(*) The occupancies for all atoms listed in this table are 1.0.

1 C9 1 I -0.7980(4) / -0.4029(3) / -0.5974(2) / 0.0505 I

I I

C10 / -0.7165(4) / -0.4310(3) / -0.6280(2) 1 0.0562

C l l / -0.7244(4) 1 -0.4797(3) 1 -0.6898(2) / 0.0564 I j

C12 1 -0.8096(3) / -0.4960(3) / -0.71947(19) 1 0.0436

I I L H72 / -0.9364(4) 1 -0.3150(4) / -0.4942(2) / 0.089(5) /

A 4 ----------------------------------: I

I H8 1 / -0.7929(4) / -0.2993(4) / -0.5303(2) / 0.084(5) / .--------------------------------+---------------------------------4-----.--.-------------------------i----------------------------------L---------------------------------i

I H82 / -0.7805(4) / -0.3881(4) / -0.4915(2) / 0.084(5) /

f-------------------------2---------------------------LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLi--------------------------------j

H l l l I 1 I -0.6713(4) / -0.5021(3) / -0.7117(2) 1 0.079(5) 1 + 4 4 '

I j H141 i -0.6853(4) 1 -0.5768(3) 1 -0.7971(2) 1 0.075(5) i

Table 8.2.3. Bond Lengths (a) for the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex

Table 8.2.4. Bond Angles (") for the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex

8.2.25. Optical Rotary Dispersion Spectrum of the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex

The following optical rotatory dispersion spectrum of the C~(267c )~CuCl~

complex was recorded at 20 OC in chloroform [c 0.0030 (g per 100 mL)] (Figure 8.2.3.).


304 nm, +1.1 I 10'

10000 - A

329 nm. -1.3 r 10'

-15000 4 200 300 400 500 600 700 800

Wavelength (nm)

Figure 8.2.3. Optical rotary dispersion spectrum of the C ~ ( 2 6 7 c ) ~ C u C l ~ Complex.


Chapter 3

8.3.1. 4-Methyl-6,7-dihydro-SH-[l]pyrindine-7-one (lS,2S)-1,2-Diphenyl-1,2-

ethanediol Acetal(300)

To a stirred solution of the 2-chloropyridine 268c (200 mg, 0.529 mmol) and

dibromobis(triphenylphosphine)nickel(II) (1 18 mg, 0.159 mmol) in anhydrous

acetonitrile (4 mL) was added potassium carbonate (80 mg, 0.58 mmol) and borane

dimethylamine complex (81 mg, 1.38 mmol) and the resultant solution was heated at 50

"C for 12 h. The reaction mixture was then allowed to cool to room temperature and was

filtered through a pad of celite and the filter cake was washed with ether (25 mL). The

combined filtrates were concentrated in vacuo to afford the crude product. Flash

chromatography using hexanes:ether (3: 1) as the eluant afforded the title compound 300

(140 mg, 77%) as a colourless oil. [a] - 122 (c 1.4, chloroform); 'H NMR (CDC13) 6

2.3 1 (3H, s, CH3), 2.62-2.70 (2H, m, ArCH2CH2), 2.90-2.97 (2H, m, ArCH2), 4.82 (lH,

d, J = 8.6 Hz, OCH), 5.59 (lH, d, J = 8.6 Hz, OCH), 7.07-7.10 (lH, m, ArH), 7.10-7.15

(IH, m, ArH), 7.21-7.25 (lH, m, ArH), 7.26-7.36 (6H, m, ArH), 7.47-7.5 1 (2H, m, Arw,

8.53 (lH, d, J = 4.9 Hz, ArH); 13c NMR (CDC13) 6 18.3, 24.3, 36.2, 86.2, 115.5, 124.9,

126.8, 127.1, 127.9, 128.3, 128.4, 128.5, 128.8, 134.0, 136.5, 136.6, 144.5, 149.5; IR

(neat) 1420, 1342, 1123, 1051, 780; MS (CI) m/z (rel. intensity) 344 (M + H, 100); Anal.

Calcd. for C23H21N02: C, 80.44; H, 6.16; N, 4.08. Found: C, 80.52; H, 6.19; N, 3.95.

ethanediol Acetal N-Oxide (299)

To a stirred solution of the pyridine 300 (125 mg, 0.364 mmol) in

dichloromethane (5 mL) was added m-chloroperoxybenzoic acid (177%, 323 mg, 1.44

mmol) and the resultant solution was stirred at room temperature for 16 h. The reaction

mixture was then diluted with dichloromethane (25 mL) and was washed with an aqueous

solution of potassium hydroxide (20% wlw, 15 mL). The organic layer was dried over

anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product.

Flash chromatography using chloroform:methanol (955) as the eluant afforded the title

compound 299 (128 mg, 99%) as a white solidlfoam. M.p. 63-64 "C,

chloroform/methanol; [a] - 242 (c 0.18, chloroform); 'H NMR (CDC13) 52.26 (3H, s,

CH3), 2.59-2.77 (2H, m, ArCHzCHz), 2.85-2.93 (2H, m, ArCH2), 4.75 (IH, d, J = 8.8 Hz,

OCH), 5.89 (lH, d, J = 8.8 Hz, OCH), 7.05 (lH, d, J = 6.4 Hz, Arm, 7.22-7.36 (8H, m,

ArH), 7.54-7.60 (2H, m, ArH), 8.08 (lH, d, J = 6.4 Hz, ArH); 13c NMR (CDC13) 6 17.5,

24.8, 37.7, 87.0, 87.3, 115.5, 126.7, 127.5, 128.2, 128.3, 128.4, 128.6, 128.9, 134.1,

135.8, 136.8, 138.9, 142.2; IR (KBr) 1461, 1327, 1258, 1202, 1174, 1139, 1086, 1062,

930, 752 cm-'; MS (CI) m/z (rel. intensity) 344 (M - 0 + H, loo), 186 (66), 149 (69);

Anal. Calcd. for C23H21N03*H20: C, 73.19; H, 6.14; N, 3.71. Found: C, 73.19; H, 6.08;

N, 3.61.

8.3.3. 4,4 '-Dimethyl-6,6 ', 7,7'-tetrahydro-SH,5 'H-2,2 '-bi((l]pyrindinyl)- 7,7'-dione

(lS,2S)-1,2-Diphenyl-1,2-ethanediol bis-Acetal N-Oxide (301)

Me, Me

To a stirred solution of the 2,2'-bipyridine 267c (100 mg, 0.145 mmol) in

dichloromethane (5 mL) was added m-chloroperoxybenzoic acid (<77%, 323 mg, 1.44

mmol) and the resultant solution was stirred at room temperature for 72 h. The reaction

mixture was then diluted with dichloromethane (25 mL) and was washed with an aqueous

solution of potassium hydroxide (20% wlw, 15 mL). The organic layer was dried over

anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product.

Flash chromatography using chloroform as the eluant afforded the title compound 301

(57 mg, 55%) as a viscous colourless oil. [a] 2 - 268 (c 0.75, chloroform); 'H NMR

(CDC13) 62.32 (6H, broad s, CH3), 2.57-2.82 (4H, m, ArCH2CH2), 2.84-2.98 (4H, m,

ArCH2), 4.69-4.76 (2H, m, OCH), 5.75-5.84 (2H, m, OCH), 7.17-7.37 (1 8H, m, ArH),

7.47-7.55 (2H, m, ArH), 8.07 (2H, broad s, ArH); 13c NMR (CDC13) G 2 1.6, 24.8, 37.9,

86.7, 87.1, 115.8, 126.7, 127.9, 128.2, 128.4, 128.6, 128.8, 129.3, 135.4; IR (neat) 2929,

1726, 1677, 1494, 1450, 1325, 1261, 1148, 700 cm-'; MS (MALDI-TOF) m/z 717 (M +

H), 701 (M - 0 + H); Anal. Calcd. for C46H40N206: C, 77.08; H, 5.62; N, 3.91. Found: C,

76.92; H, 5.93; N, 3.95.

8.3.4. Asymmetric Synthesis of (lS,2S)-2-Chloro-1,2-diphenyletizan-l-ol(303)

To a stirred solution of the chiral pyridine-N-oxide 299 (28 mg, 79 pmol), cis-

stilbeneoxide meso-302 (155 mg, 0.79 mmol) and NjV-diisopropylethylamine (151 pL,

0.869 mmol) in dichloromethane (3 mL) at -78 "C was added silicon tetrachloride (1 10

pL, 0.948 mmol) and the resultant solution was stirred at -78 "C for 24 h. The reaction

mixture was then allowed to warm to 0 "C and then a mixture (1: 1, 3 mL) of a saturated

aqueous solution of potassium fluoride and an aqueous solution of potassium hydrogen

phosphate (1.0 M) was added. The resultant mixture was then extracted with ethyl

acetate (3 x 10 mL). The combined organic extracts were washed with water (5 mL),

dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude

product. Flash chromatography using hexanes:ether (9: 1) as the eluant afforded the title

compound 303 (162 mg, 88%) as a colourless oil. The enantiomeric purity of this

material was determined to be 22% ee by analytical chiral GC using a J & W Scientific

CYCLOSILB column [column temp. 170 "C, head pressure 20 psi; t ~ p g o ~ = 75.97 min,

~MNOR = 77.74 min]. [a] + 3.1 (c 1.1, ethanol) [lit.'79 - 20.2 (c = 5.2, ethanol) for R,R-

enantiomer]; 'H NMR (CDC13) 6 3.02 (lH, d, J = 2.8 Hz, ClCH), 4.95 (lH, dd, J = 8.3,

2.7 Hz, HOCH), 5.01 (IH, d, J = 8.3 Hz, OH), 7.08-7.13 (2H, m, ArH), 7.14-7.24 (SH,

m, ArH); 13c NMR (CDC13) 6 70.67, 78.76, 126.96. 127.96, 128.14, 128.20, 128.32,

128.55, 137.67, 138.68; MS (CI) m/z (rel. intensity) 2 15 (M - OH, 100).

(179) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. Enantioselective Ring Opening of

Epoxides with Silicon Tetrachloride in the Presence of a Chiral Lewis Base. J. Org. Chem. 1998, 63,2428.


Chapter 4

8.4.1. 2-(2-Fluorophenyl)-4-methyl-6,7-dihydro-SH-(llpyrindine- 7-one (2R,3R)-2,3-

Butanediol Acetal(305a)

To a stirred solution of the acetal 268a (100 mg, 0.395 mmol) and ortho-

fluorophenylboronic acid 306 (83 mg, 0.59 mmol) in degassed tetrahydrofuran (10 mL)

was added tris(dibenzylideneacetone)dipalladium(O) (18 mg, 20 pmol), tri-tert-

butylphosphine (395 pL of a 0.10 M solution in tetrahydrofuran, 40 pmol) and anhydrous

cesium carbonate (641 mg, 1.97 mmol). The resultant suspension was heated at reflux

for 16 h. The reaction mixture was then allowed to cool to room temperature and was

then diluted with ethyl acetate (25 mL). The resultant solution was washed with brine

(1 0 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the


title compound 305a (1 15 mg, 93%) as a white crystalline solid. M.p. 63-64 "C,

hexaneslether; [a] - 45.2 (c 0.87, chloroform); 'H NMR (CDC13) S 1.22 (3H, d, J = 6.1


ArCH2CH2), 2.50-2.56 (2H, m, ArCH2), 3.86 (lH, dq, J = 5.8, 7.9 Hz, OCH), 4.85 (lH,

dq, J = 6.1, 8.2 Hz, OCH), 6.95-7.01 (2H, m, ArH), 7.04-7.09 (1 H, m, ArH), 7.50-7.53

(lH, m, ArH), 8.35-8.41 (lH, m, ArH); 13c NMR (C6D6) 6 17.4, 18.4, 18.8, 24.6, 36.7,

79.7, 80.6, 115.4, 116.8, 117.0, 125.1, 125.2, 125.86, 125.94, 130.6, 130.7, 132.30,

132.33, 135.0, 144.7, 153.4, 162.9, 163.6; IR (KBr) 2973, 2928, 1599, 1493, 1450, 1377,

1348, 1318, 1293, 1275, 1266, 1240, 1211, 1190, 1180, 1158, 1098, 1080, 1047, 935,

898, 882, 761 cm-'; MS (CI) m/z (rel. intensity) 314 (M + H, loo), 242 (14); Anal. Calcd.

for Cl9HZ0FNO2: C, 72.82; H, 6.43; N, 4.47. Found: C, 72.55; H, 6.54; N, 4.33.

8.4.2. 2-(2-Fluorophenyl)-4-methyl-6,7-dihydro-SH-flJpyrindine- 7-one (1 S,2S)-1,2-

Diisopropyl-1,2-ethanediol Acetal(305b)

To a stirred solution of the acetal 268b (100 mg, 0.323 mmol) and ortho-


was added tris(dibenzylideneacetone)dipalladium(0) (14 mg, 16 pmol), tri-tert-


cesium carbonate (525 mg, 1.62 mmol). The resultant suspension was then heated at

reflux for 16 h. The reaction mixture was then allowed to cool to room temperature and

was diluted with ethyl acetate (25 mL). The resultant solution was washed with brine (10



title compound 305b (97 mg, 81%) as a colourless oil. [a] - 4.38 (c 0.64, chloroform);

'H NMR (CDC13) 60.98 (3H, d, J = 6.6 Hz, CHCH3), 1.00 (3H, d, J = 7.3 Hz, CHCH3),

1.02-1.07 (6H, m, 2 x CHCH3), 1.83-1.91 (lH, m, CHCH3), 2.32 (3H, s, CH3), 2.38-2.45

(3H, m, ArCH2CH2 and CHCH3), 2.83-2.88 (2H, m, ArCH2), 3.7 1 (lH, dd, J = 5.9, 7.3

Hz, OCH), 4.15 (IH, apparent t, J = 5.1 Hz, OCH), 7.09-7.19 (lH, m, Arm, 7.20-7.25

(lH, m, ArH), 7.30-7.42 (lH, m, Arm, 7.54 (lH, s, ArH), 7.99-8.04 (IH, m, ArH); I3c

NMR (CDC13) 6 17.9, 18.7, 19.2, 19.7, 20.1, 24.3, 31.7, 31.8, 37.2, 86.0, 86.3, 115.6,

116.2, 116.4, 124.6, 125.6, 125.7, 130.07, 130.14, 131.7, 135.1, 144.5; IR (KBr) 2963,

1654, 1596, 1560, 1542, 1507, 1490, 1459, 1321, 1179, 1098, 1057, 924, 931, 761 cm-';

MS (CI) m/z (rel. intensity) 370 (M + H, 1 OO), 242 (19), 19 1 (14), 190 (13); Anal. Calcd.

for C23H28FN02: C, 74.77; H, 7.64; N, 3.79. Found: C, 74.9 1; H, 7.52; N, 3.56.

8.4.3. 2-(2-Fluorophenyl)-4-methyl-6,7-dihydro-SH-(l/pyrindine- 7-one (IS,2S)-1,2-

Diphenyl-1,2-ethanediol Acetal(305c)

Me\

To a stirred solution of the acetal 268c (351 mg, 0.929 mmol) and ortho-


was added tris(dibenzylideneacetone)dipalladium(0) (41 mg, 46 pmol), tri-tert-


cesium carbonate (1.51 g, 4.63 mmol). The resultant suspension was then heated at

reflux for 16 h. The reaction mixture was then allowed to cool to room temperature and

was diluted with ethyl acetate (15 mL). The resultant solution was washed with brine (10



title compound 305c (356 mg, 88%) as a white foadsolid. M.p. 46-48 "C,

hexaneslether; [a] + 119 (c 0.56, chloroform); 'H NMR (CDC13) 52.36 (3H, s, CH3),

2.64-2.79 (2H, m, ArCH2CH2), 2.94-3.02 (2H, m, ArCH2), 4.87 (lH, d, J = 8.6 Hz,

OCH), 5.72 (lH, d, J = 8.60 Hz, OCH), 7.14-7.21 (lH, m, ArH), 7.27-7.34 (9H, m, ArH),

7.35-7.42 (lH, m, ArH), 7.62-7.69 (3H, m, ArH), 8.12-8.17 (lH, m, ArH); 13c NMR

(CDC13) 541.8, 52.2, 55.4, 61.6, 75.8, 110.6, 120.9, 123.6, 127.9, 128.59, 128.62, 128.8,

128.9, 129.5, 129.9, 131.2, 134.3, 157.2, 157.9, 167.3; MS (CI) m/z (rel. intensity) 438

(M + H, 25), 331 (6), 242 (loo), 197 (19), 169 (1 I), 146 (8), 113 (22), 81 (59); Anal.

Calcd. for C29H24FN02: C, 79.61; H, 5.53; N, 3.20. Found: C, 79.90; H, 5.52; N, 3.41.

8.4.4. 2-(2-Diphenylphosphanyl-phenyI)-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one

To a stirred solution of potassium tert-butoxide (101 mg, 0.900 mmo 11) and 18-

crown-6 (283 mg, 1.07 mmol) in tetrahydrofuran (5 mL) at 0 "C was added

diphenylphosphine (166 mg, 0.892 mmol). The resultant red solution was stirred for 1 h.

A solution of the aromatic fluoride 305a (140 mg, 0.446 mmol) in tetrahydrofuran (2 mL)

was then added via a cannula and the resultant mixture was stirred at room temperature

for 24 h. Methanol (2 mL) was then added and the solution was concentrated in vacuo to

afford the crude product. Flash chromatography using hexanes:ether (8: 1) as the eluant

afforded the title compound 304a (155 mg, 72%) as a white foadsolid. M.p. 48-49 "C,

hexaneslether; [a] + 1.96 (c 0.53, chloroform); 'H NMR (C6D6) 6 1.15 (3H, d, J = 6.1


CH2), 2.46-2.54 (2H, m, CH2), 3.73-3.80 (lH, m, CHCH3), 4.42-4.51 (IH, m, CHCH3),

7.02-7.1 1 (8H, m, ArH), 7.23-7.26 (IH, m, ArH), 7.37-7.46 (5H, m, ArH), 7.76 (IH, ddd,

J = 1.5, 4.6, 7.9 HZ, Arm; 13c NMR (C6D6) S 16.6, 17.6, 17.7, 23.9, 36.5, 78.9, 79.8,

114.7, 125.7, 125.8, 127.8, 128.5, 128.6, 128.9, 129.9, 130.6, 130.7, 134.0, 134.2, 134.3,

134.4, 134.5, 135.5, 139.4, 139.6, 143.1, 159.2, 162.4; IR (KBr) 3050, 2970, 2928, 1597,

1585, 1477, 1433, 1374, 1347, 1315, 1277, 1137, 1190, 1157, 1126, 1100, 1081, 936,

766, 744, 697, 627 cm-l; MS (CI) m/z (rel. intensity) 480 (M + H, loo), 409 (16), 402

(17); Anal. Calcd. for C31H30N02P: C, 77.64; H, 6.3 1; N, 2.92. Found: C, 77.39; H, 6.49;

N, 2.67.

8.4.5. 2-(2-Diphenylphosphanyl-phenyl)-kmethyl-6,7-dihydro-5H-[ljpyrindine- 7-one

(lS,2S)-1,2-Diisopropyl-1,2-ethanediol Acetal(304b)

Me\

To a stirred solution of potassium tert-butoxide (256 mg, 2.26 mmol) and 18-

crown-6 (717 mg, 2.71 mmol) in tetrahydrofuran (10 mL) at 0 OC was added


A solution of the aromatic fluoride 305b (4 17 mg, 1.13 mmol) in tetrahydrofuran (5 mL)

was then added via a cannula and resultant mixture was stirred at room temperature for

24 h. Methanol (5 mL) was then added and the solution was concentrated in vacuo to


afforded the title compound 304b (402 mg, 66%) as a white foarnlsolid. M.p. 54-55 OC,

hexanedether; [a] - 8.33 (c 0.60, chloroform); 'H NMR (CDC13) 60.87 (3H, d, J = 7.0

Hz, CHCH3), 0.93 (3H, d, J = 6.4 Hz, CHCH3), 0.97 (3H, d, J = 7.0 Hz, CHCH3), 1 .O1

(3H, d, J = 6.7 Hz, CHCH3), 1.75-1.85 (lH, m, CH(CH3)2), 2.10 (3H, s, CH3), 2.19-2.29

(lH, m, CH(CH3)2), 2.33-2.41 (2H, m, ArCH2CH2), 2.76-2.84 (2H, m, ArCH2), 3.59 (lH,

dd, J = 5.8, 7.9 Hz, OCH), 4.00-4.08 (lH, m, OCH), 6.93 (lH, s, ArH), 7.1 1 (lH, ddd, J

= 1.2, 4.0, 7.6 Hz, ArH), 7.21-7.31 (7H, m, ArH), 7.31-7.36 (5H, m, ArH), 7.39-7.45

(lH, m, ArH), 7.62-7.67 (lH, m, ArH); 13c NMR (CDC13) 6 17.8, 18.5, 19.4, 19.8, 20.2,

24.3, 31.5, 37.4, 85.9, 128.57, 128.60, 128.65, 128.76, 128.79, 129.1, 131.0, 134.1, 134.2,

134.3, 134.4, 135.2; IR (KBr) 3447, 2959, 2919, 2864, 2366, 2341, 1655, 1591, 1541,

1490, 1447, 1434, 1344, 1311, 1254, 1218, 1102, 1073, 921, 744, 698 cm-'; MS

(MALDI-TOF) 537 (M + H); Anal. Calcd. for C35H38N02P: C, 78.48; H, 7.15; N, 2.61.

Found: C, 78.39; H, 7.25; N, 2.69.

8.4.6. 2-(2-Diphenylphosphanyl-ph enyo-4-methyl-, 7-dihydro-SH-[I Jpyrindine- 7-one

(1 S,2S)-1,2-Diphenyl-l,2-ethanediol Acetal(304c)

Me

To a stirred solution of potassium tert-butoxide (177 mg, 1.58 mmol) and 18-

crown-6 (502 mg, 1.90 mmol) in tetrahydrofuran (12 mL) at 0 OC was added


A solution of the aromatic fluoride 305b (346 mg, 0.791 mmol) in tetrahydrofuran (5

mL) was then added via a cannula and resultant mixture was stirred at room temperature

for 24 h. Methanol (5 mL) was added and the solution was concentrated in vacuo to


afforded the title compound 304c (302 mg, 63%) as a white foadsolid. M.p. 79-80 "C,

hexaneslether; [a] - 129 (c 0.55, chloroform); 'H NMR (CDC13) 52.16 (3H, s, CH3),

2.55-2.75 (2H, m, ArCH2CH2), 2.83-2.97 (2H, m, ArCH2), 4.75 (lH, d, J = 8.7 Hz,

OCH), 5.38 (lH, d, J = 8.7 Hz, OCH), 7.04-7.06 (lH, m, ArH), 7.12-7.35 (20H, m, ArH),

7.47 (lH, m, ArH), 7.56-7.62 (2H, m, ArH), 7.73 (lH, ddd, J = 1.1, 4.4, 7.6 Hz, ArH);

13c NMR (CDC13) 5 18.4, 24.3, 36.5, 85.5, 86.5, 115.7, 126.5, 126.6, 126.9, 128.2,

760,746,698 cm-'; MS (MALDI-TOF) 605 (M + H); Anal. Calcd. for C41H34N02P: C,

8l.57;H,5.68;N72.32.Found: C781.63;H,5.72;N,2.33.

8.4.7. Procedure for Palladium(0)-Catalyzed Asymmetric Heck Reactions:

Asymmetric Synthesis of (2s)-2,s-Dihydro-2-phenylfuran (S-309)

1.5 mol % Pd2dba3 3 mol % P, N-ligand 304a-c

(i-PrhNEt, benzene, 70 "C, 3 days PhOTf w

up to 59%

A solution of tris(dibenzylideneacetone)dipalladium(0) (24 mg, 26 pmol) and the

chiral P,N-ligand 304a-c (52 pmol) in anhydrous, degassed benzene (10 mL) was stirred

at room temperature for 1 h. Phenyl triflate 308 (0.28 mL, 1.7 mmol), 2,3-dihydrofuran

307 (0.66 mL, 8.7 mmol) and N,N-diisopropylethylamine (0.91 mL, 5.2 mmol) were then

added and the resultant solution was heated at 70 OC for 72 h. The reaction mixture was

then allowed to cool to room temperature and was diluted with ether (50 mL). The

organic layer was washed with brine (2 x 10 mL), dned over anhydrous magnesium

sulfate and concentrated in vacuo to afford the crude product. For the reaction that

employed the P,N-ligand 304a (R = Me), the crude product was purified by flash

chromatography using hexaneslether (4:l) as the eluant which afforded the title

compound (9-309 (150 mg, 59%) as a colourless oil. The enantiomeric purity of this

material was determined to be 22% ee and the absolute stereochemistry was determined

to be ( 9 by comparison of the optical rotation with the literature value. [a]: - 62 (c

1.50, chloroform) [lit.la0 -265 (c 0.925, chloroform, 91% ee by chiral GC)]; 'H NMR

(CDC13) 6 4.71-4.8 1 (lH, m, CHH), 4.80-4.89 (lH, my CHH), 5.76-5.82 (lH, m, OCH),

13 5.98-6.02 (2H, m, 2 x CH), 7.23-7.39 (5H, m, ArH); C NMR (CDC13) 676.2, 88.3,

126.4, 126.5, 127.6, 127.7, 128.4, 129.9, 142.1; IR (neat) 2955, 2852, 1600, 1492 cm-';

MS (CI) m/z (rel. intensity) 147 (M + H, 100).

(180) Kiindig, P. E.; Meier, P. Synthesis of New Chiral Bidentate (Phosphinopheny1)benzoxazine P,N-

Ligands. Helv. Chim. Acta 1999,82, 1360.

8.4.8. General Procedures for Palladium(1I)-Catalyzed Asymmetric Allylic

Substitution Reactions: Asymmetric Synthesis of (1R)-(1,3-Diphenyla1lyl)malonic

Acid Dimethyl Ester (R)-312 and (IS)-(1,3-Diphenyla1lyl)malonic Acid Dimethyl Ester

Me02C,,C02Me 31 1 2.5 mol % [ P ~ C I ( ~ ~ - C ~ H ~ ) ] ~ (3 equiv) 6.25 mol % P,N-ligand 304a-c M e o 2 C ~ Co2Me

baseladditives, CH2CI2 t Ph 4 P h

OAc Ah (RS)-310 (R)-312 and (S)-312 Ph

A solution of allylpalladium(II) chloride dimer (3.7 mg, 10 pmol) and the chiral

P,N-ligand 304a-c (25 pmol) in dichloromethane (1.5 mL) was stirred at room

temperature for 1 h. A solution of (3RS)-3-acetoxy- l,3-diphenyl- 1 -propene RS-310 (1 00

mg, 0.396 mmol) and dimethyl malonate 311 (208 mg, 1.20 mmol) in dichloromethane

(1.5 mL) was then added via a cannula followed by one of three bases and associated

reagents [(I) BSA (295 pL, 1.20 mmol) and a catalytic amount of potassium acetate (3

mg); (2) potassium carbonate (166 mg, 1.20 mmol) and 18-crown-6 (296 mg, 1.20

mmol); (3) anhydrous cesium carbonate (391 mg, 1.20 mmol)]. The reaction mixture

was then stirred at the temperature specified (see Table 4.5.1., Chapter 4) and was

monitored by thin-layer chromatography until the starting material had been consumed.

The reaction mixture was then diluted with ether (25 mL) and washed with a saturated

aqueous solution of ammonium chloride (5 mL) and water (5 mL). The organic layer

was then dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the

crude product. Flash chromatography using hexanesether (3: 1) as the eluant afforded the

title compounds (R)-312 or (9-312 as colourless oils. The enantiomeric purity of the

reaction products was determined by analytical chiral HPLC (Daicel Chiracel OD

column) [hexanes:2-propanol (97:3), flow rate at 0.5 mLImin, detector at A = 245 nm; tl

= 19.4 min, t2 = 20.5 min]. The absolute stereochemistry of the reaction products was

determined by comparing the sign of the optical rotation to a literature value.181 'H

NMR (CDC13) 63.53 (3H, S, C02CH3), 3.71 (3H, S, C02CH3), 3.96 (lH, d, J = 10.7 HZ,

CH(C02CH3)2), 4.27 (lH, dd, J = 11.0, 8.6 HZ, ArCH), 6.33 (lH, dd, J = 15.9, 8.6 HZ,

CH), 6.48 (lH, d, J = 15.9 Hz, CH), 7.17-7.35 (lOH, m, ArH); 13c NMR (CDC13) 649.2,

52.4, 52.6, 57.6, 126.4, 127.2, 127.6, 127.9, 128.5, 128.7, 129.1, 131.8, 136.8, 140.2,

167.8, 168.2; IR (KBr) 1759, 1733, 1600, 1494, 1433, 1321, 1261, 1141, 1020,968,921,

803, 766,745, 700 cm-'; MS (CI) m/z (rel. intensity) 324 (M + H, 3), 235 (lo), 193 (100).

8.4.9. Crystallization of the P,N-Ligand (304c)*

The P, 304c (20 mg, 33 pmol) and mercury(I1) cyanide (8.3 mg, 33

pmol) were dissolved in ethano1:dichloromethane (1: 1, 5 mL). Upon slow evaporation of

the solvent mixture, colourless X-ray quality crystals of the P,N-ligand 304c were

deposited from the solution.

(181) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; GagnC, M. R. Application of Chiral

Mixed Phosphorus/Sulfir Ligands to Palladium-Catalyzed Allylic Substitutions. J. Am. Chem. Soc. 2000,

122,7905.

(*) This procedure was conducted by Mr Neil D. Draper of Professor Daniel B. Leznoff s research group at

Simon Fraser University in an attempt to synthesize a chiral coordination polymer of the P,N-ligand 304c

and mercury(I1) chloride, see: Chapter 4, Section 4.3.

8.4.10. X-Ray Crystallographic Analysis of the P,N-Ligand (304c)

A single crystal, a colourless block that had the dimensions 0.43 x 0.57 x 0.68

mm3, was mounted on a glass fiber using epoxy adhesive. The data for this crystal of the

P,N-ligand 304c was acquired at 293 K on an Enraf Nonius CAD4F diffractometer using

graphite monochromated Mo K a radiation. The following data range was recorded: 4" 5

20 5 50". The data was corrected by integration for the effects of absorption using a

semi-empirical psi-scan method with the following transmission range: 0.8730 - 0.9819.

The data reduction included corrections for Lorentz and polarization effects. Final unit-

cell dimensions were determined based on the following well-centred reflections: 42

reflections with range 38" 1 2 0 5 42".

For the Pa-ligand 304c, the coordinates and anisotropic displacement parameters for

the non-carbon and hydrogen atoms were refined; carbon atoms were refined using

isotropic thermal parameters. Hydrogen atoms were placed in calculated positions (d C-

H 0.95 A) and their coordinate shifts were linked with those of the respective carbon

atoms during refinement. Isotropic thermal parameters for the hydrogen atoms were

initially assigned proportionately to the equivalent isotropic thermal parameters of their

respective carbon atoms. Subsequently, the isotropic thermal parameters for the C-H

hydrogen atoms were constrained to have identical shifts during refinement.

The programs used for all absorption corrections, data reduction, and processing

were from the NRCVAX Crystal Structure stern."^ The structure was refined using

CRYSTALS. '77 An ORTEP representation of the P,N-ligand 304c is provided below

(Figure 8.4.1 .). Crystallographic data, fractional atomic coordinates and equivalent

(1 82) Gabe, E. J.; Lepage, Y.; Charland, J. P.; Lee, F. L.; White, P. S. J. Appl. Cyst. 1989, 22, 384-387.

258

isotropic thermal displacement parameters, selected bond lengths, and selected bond

angles for the P,N-ligand 304c are also listed below (Table 8.4. l., 8.4.2., 8.4.3. and 8.4.4.,

respectively).

Figure 8.4.1. ORTEP representation of the P,N-ligand 304c.'

(*) Thc thermal ellipsoids are drawn at a 25% probability level for clarity.

Table 8.4.1. Summary of Crystallographic Data for the P,N-ligand 304c

Empirical formula C4 1H34N02P

F W (g mol-') 1206.27

Temperature (K) 293

Wavelength (Cu Ka, A) 1 .541 80

Crystal system

Independent reflections

Reflections observed [I = 2.50(0]

Goodness-of-fit on F

R1, Rw [ I = 2.5401

monoclinic


Parameters [U(iso), (A2)] for the P,N-Ligand 304c'

atom x Y z U (iso)

/ C8 ( -0.4893(4) / -0.4883(5) 1 -0.8941(2) / 0.0507 / I I

I I L-------------------L-------------------------------------+-------------------------------------- I----II--IIIIIIIIIIIIIIIIIIIIIIII----..IIIIIIIIIIIIIIIIIIIIIIII....I.IIIII I C9 / -0.3937(4) 1 -0.5234(5) / -0.8871(2) / 0.0461 i I I I I

I :----- -------------- L 4 ----------------.--------------------- ~CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC~ --------------..-----------------+

1 ClO / -0.3657(4) / -0.6501(5) 1 I -0.8664(2) 1 I 0.0456 1 I

] C l l 1 -0.3200(4) / -0.7209(6) -0.9041(3) 1 0.0579 1 I

;---------.-...-------------------L 4

I I C12 / -0.3028(4) / -0.8410(6) / -0.8904(3) / 0.0626 1 I 1

1 C13 / -0.3284(4) / -0.8922(5) / -0.8395(3) ] 0.0625

- -

(*) The occupancies for all atoms listed in this table are 1 .O.

H l l l 1 -0.3005(4) 1 -0.6860(6) 1 -0.9392(3) / 0.071(4)

8.4.11. Procedure for the Preparation and Crystallization of the PdC12.P,N-Ligand

(304a) Complex

A solution of the ligand 304a (20 mg, 42 pmol) and palladium(I1) chloride (7.4

mg, 42 pmol) in acetonitrile (2 mL) was heated at reflux for 30 min. The reaction

mixture was then allowed to cool to room temperature and was concentrated in vacuo to

afford the crude product. This material was then dissolved in hot ethanol (I mL) and

upon cooling to 5 OC, the title compound (21 mg, 77%) was obtained as orange X-ray

quality crystals. M.p. >210 OC (dec.), ethanol; [a] - 55 (c 0.15, chloroform); IR (KBr)

2362, 2340, 1996, 1656, 1610, 1561, 1547, 1438, 1090, 1074 873 cm-I; MS (MALDI-

TOF) m/z 620 (M - Cl); Anal. Calcd. for C31H30C12N02PPd: C, 56.68; H, 4.60; N, 2.13.

Found: C, 56.3 1; H, 4.42; N, 2.27.

8.4.12. X-Ray Crystallographic Analysis of the PdClz-P,N-Ligand (304a) Complex

A single crystal, an orange platelet that had the dimensions 0.09 x 0.26 x 0.26

mm3, was mounted on a glass fiber using epoxy adhesive. The data for this crystal of the

palladium(I1) chloride Pa-ligand 304a complex was acquired at 293 K on an Enraf

Nonius CAD4F diffractometer with graphite monochromated Mo K a radiation. The

following data range was recorded: 4" 1 28 1 46". The data was corrected by integration

for the effects of absorption using a semi-empirical psi-scan method with the following

transmission range: 0.5362 - 0.915 1. The data reduction included corrections for Lorentz

and polarization effects. Final unit-cell dimensions were determined based on the

following well-centred reflections: 56 reflections with range 30" 1 28 138" .

The coordinates and anisotropic displacement parameters for the non-carbon and

hydrogen atoms were refined. Carbon atoms were refined using isotropic thermal

parameters. Hydrogen atoms were placed in calculated positions (d C-H 0.95 A) and

their coordinate shifts were linked with those of the respective carbon atoms during

refinement. Isotropic thermal parameters for the hydrogen atoms were initially assigned

proportionately to the equivalent isotropic thermal parameters of their respective carbon

atoms. Subsequently the isotropic thermal parameters for the C-H hydrogen atoms were

constrained to have identical shifts during refinement. The programs used for all

absorption corrections, data reduction, and processing were from the NRCVAX Crystal

Structure The structure was refined using CRYSTALS. '77

An ORTEP representation of the palladium(I1) chloride Pa-ligand 304a complex

is provided below (Figure 8.4.2.). Crystallographic data, fractional atomic coordinates

and equivalent isotropic thermal displacement parameters, selected bond lengths, and

selected bond angles for the palladium(II) chloride P,N-ligand 304a complex are also

listed below (Table 8.4.5., 8.4.6., 8.4.7. and 8.4.8., respectively).

Figure 8.4.2. ORTEP representation of the PdC12-P,N-ligand 304a complex.'

Table 8.4.5. Summary of Crystallographic Data for the PdC12-P,N-ligand 304a Complex

Empirical formula C3, H30NC1202PPd

F W (g mol") 656.8746

Temperature (K)

Crystal system

Space group

a (4

293

orthorhombic

p 21 21 21

1 l.6538(13)

(*) Thc thermal ellipsoids are drawn at a 25% probability level for clarity.

b (4

c (4

a (O)

P (O)

r C')

z

u (A3>

Dcalc (g

20 limits (")

Reflections collected

Independent reflections

Reflections observed [I = 2.5a(l)]

Goodness-of-fit on F

R1, Rw [I= 2.50(l)]


Parameters [U(iso), (A2)] for the PdClyP,N-ligand 304a Complex*

Atom x Y z U (iso) I Pdl 1 0.70704(12) / 0.24533(17) / 0.28174(8) 0.0492

:


Table 8.4.7. Bond Lengths (A) for the PdClyP,N-ligand 304a Complex

Pdl -C11 2.376(6)

I Pdl -C12

Pdl -N1 2.067(14)

Table 8.4.8. Bond Angles (") for the PdCI2- P,N-ligand 304a Complex

Pdl-PI-C18 98.2(6) I I

I I Pd l -P 1-C20 1 15.4(8) I

I I

108.0(11) C18-PI-C20 I

Pdl -P 1 -C26 I 122.5(7) I

C18-PI-C26 104.2(10) 1

8.4.13. 2-(2-Diphenylphosphanyl-phenyl)-4-methyl-6,7-dihydro-SH-(l/pyrindine-7-one

(2R,3R)-2,3-Butanediol Acetal Iridium(1) Cyclooctadiene tetrakis(3J-

bis(TriJ2uoromethyl)phenylJborate Complex (324a)

A deep orange solution of the P,N-ligand 304a (18 mg, 38 pmol) and

cyclooctadieneiridium(I) chloride dimer (13 mg, 19 pmol) in anhydrous dichloromethane

(3 mL) was heated at reflux for 1 h. The reaction mixture was then allowed to cool to

room temperature and sodium tetvakis[3,5-bis(trifluoromethyl)phenyl]borate (50 mg, 56

pmol) and water (3 mL) were added. The resultant biphasic mixture was stirred

vigorously for 15 min. The two phases were then separated and the aqueous phase was

extracted with dichloromethane (2 x 10 mL). The combined organic extracts were

washed with water (10 mL) and concentrated in vacuo to afford the crude product. This

material was then taken up in ethanol (1 mL) and crystallized by the slow addition of

water (1 mL) which afforded the title compound 324a (56 mg, 89%) as an orange

crystalline solid. Anal. Calcd. for C71H54BF241rN02P: C, 5 1 .go; H, 3.3 1; N, 0.85. Found:

C, 52.23; H, 3.49; N, 0.78.

8.4.14. 2-(2-Diphenylphosphanyl-phenyl)-4-methyl-6,7-dihydro-5H-[lJpyrindine-7-one

(1 S,2S)-1,2-Diisopropylethanediol Acetal Iridium (l) Cyclooctadiene te trakis[3,5-

bis(TriJluoromethyl)phenylJborate Complex (324b)

A deep orange solution of the P,N-ligand 304b (71 mg, 0.13 mmol) and


(4 mL) was heated at reflux for 1 h. The reaction mixture was then allowed to cool to

room temperature and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (177 mg,

0.20 mmol) and water (4 mL) were added. The resultant biphasic mixture was stirred





water (2 mL) which afforded the title compound 324b (219 mg, 97%) as an orange

crystalline solid. Anal. Calcd. for C75H62BF2JrN02P: C, 53.01; H, 3.68; N, 0.82. Found:

C, 53.26; H, 3. 53; N, 0.78.

8.4.15. 2-(2-Diphenylphosphartyl-phenyI)-4-methyl-6,7-dihydro-SH-[l]pyrindine- 7-one

(1 S,2S)-1,2-DiphenyI-1,2-ethanediol A cetal Iridium(0 Cyclooctadiene tetrakis[3,5-

bis(TriJuoromethyl)phenyl]borate Complex (324c)

A deep orange solution of the P,N-ligand 304c (80 mg, 0.13 mmol) and


(4 mL) was heated at reflux for 1 h. The reaction mixture was allowed to cool to room

temperature and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (177 mg, 0.20

mmol) and water (4 mL) were added. The resultant biphasic mixture was stirred





water (2 mL) which afforded the title compound 324c (211 mg, 92%) as an orange

crystalline solid. Anal. Calcd. for C81H58BF241rN02P: C, 55.05; H, 3.31; N, 0.79. Found:

C, 55.17; H, 3. 20;N, 0.65.


Chapter 5

A stirred solution of the acetate 282 (901 mg, 3.99 mmol) in concentrated sulfuric

acid (1.5 mL) was heated at 120 OC for 10 min. The reaction mixture was then poured on

to ice (-25 g) and was basified with an aqueous solution of potassium hydroxide (40%

W/V, 6 mL). The resultant mixture was extracted with dichloromethane (3 x 25 mL) and

the combined organic extracts were washed with water (2 x 10 mL), dried over

anhydrous magnesium sulfate and concentrated in vacuo to afford the crude product as a

dark brown oil. Flash chromatography using hexanes:ether (1: 1) as the eluant afforded

the title compound 336 (535 mg, 81%) as a colourless oil. 'H NMR (CDC13) 62.36 (3H,

s, CH3), 3.29-3.32 (2H, m, ArCH2), 6.91-6.98 (3H, m, 2 x CH and ArH); I3c NMR

(CDC13) 635.5, 38.4, 120.1, 133.1, 134.6, 139.9, 144.1, 149.7, 163.9; IR (neat) 2919,

1595, 1576, 1550, 1430, 1375, 1333, 1261, 1179, 11 16, 1032, 940, 892, 848 cm-'; MS

(CI) m/z (rel. intensity) 166 (M + H, 100). This material was used immediately in the

subsequent dihydroxylation reactions.

Method A: To a stirred solution of the chloropyridine 336 (101 mg, 0.604 mmol)

in tert-butano1:water (1: 1, 6 mL) at 0 OC was added AD-mix-P (840 mg) in one portion

and the resultant orange suspension was stirred at 0 OC for 12 h. Sodium sulfite (300 mg)

was then added to the reaction mixture. After an additional 30 min, brine (15 mL) was

added and the reaction mixture was extracted with ethyl acetate (3 x 25 mL). The

combined organic extracts were washed with brine (10 mL), dried over anhydrous

magnesium sulfate and concentrated in vacuo to afford the crude diol (+)-335 as a light

brown solid. This material was taken up in benzene (6 mL) and 3-pentanone (78 pL, 0.75

mmol) and p-toluenesulfonic acid monohydrate (10 mg, 75 pmol) were added. The

resultant solution was then heated at reflux in a Dean-Stark trap for 16 h. The reaction

mixture was then allowed to cool to room temperature and potassium carbonate (20 mg)

was added. The reaction mixture was filtered, the filter-cake was washed with

dichloromethane (10 mL) and the combined filtrates were concentrated in vacuo to afford

the crude product as a dark brown oil. Flash chromatography using hexanes:ethyl acetate

(2: 1) as the eluant afforded the title compound (+)-334 (92 mg, 57%, over two steps) as a

colourless oil which crystallized upon standing. The enantiomeric purity of this material

was determined to be 90% ee by analytical chiral HPLC using a Daicel Chiracel OD

column [hexanes:isopropanol (96:4), flow rate at 0.5 mL/min, detection at A = 220 nm;

~ M ~ M ) R = 18.99 min, MINOR = 23.10 min]. The above procedure was also carried out using

AD-mix-a. The enantiomeric purity of the product of this reaction, following conversion

to the acetal (-)-334 (48% yield, over two steps), was also determined by analytical chiral

HPLC (82% ee). Acetal (+)-334: M.p. 43-44 "C; [a] 2 + 80 (c 0.50, chloroform); 'H

NMR (CDC13) 60.58 (3H, t, J = 7.3 HZ, CH2CH3), 0.94 (3H, t, J = 7.6 HZ, CH2CH3),

1.50 (2H, q, J = 7.3 Hz, CH2CH3), 1.68 (2H, q, J = 7.6 Hz, CH2CH3), 2.26 (3H, s,

ArCH3), 2.99-3.03 (2H, m, CH2), 4.98-5.02 (lH, m, HCO), 5.41 (lH, d, J = 5.8 Hz,

HCO), 7.06 (lH, s, ArH); 13c NMR (CDC13) 6 7.7, 8.9, 19.0, 29.6, 30.2, 34.34, 77.7,

83.3, 115.9, 124.8, 133.0, 148.0, 151.6, 160.9; IR (KBr) 2973, 2939, 1748, 1717, 1589,

1570, 1463, 1442, 1377, 1314, 1286, 1267, 1191, 1169, 1131, 1104, 1084, 1011,862 cm-

'; MS (CI) m/z (rel. intensity) 268 (M + H, loo), 239 (48), 182 (97); Anal. Calcd. for

C14H18ClN02: C, 62.80; H, 6.78; N, 5.23. Found: C, 62.65; H, 6.85; N, 5.35.

Method B: To a suspension of potassium osmate dihydrate (2.8 mg, 7.6 pmol, 1

mol %), (DHQD)2PHAL (29 mg, 38 pmol, 5 mol %), potassium ferricyanide (746 mg,

2.27 mmol) and potassium carbonate (313 mg, 2.27 mmol) in tert-butano1:water (1:1, 6

mL) at 0 "C was added the chloropyridine 336 (125 mg, 0.755 mmol). After 2 h, sodium

sulfite (300 mg) was added to the reaction mixture. After an additional 30 min, brine (30

mL) was added, the reaction mixture was extracted with ethyl acetate (3 x 25 mL). The

combined organic extracts were then washed with brine (10 mL), dried over anhydrous

magnesium sulfate and concentrated in vacuo to afford the crude diol (+)-335 as a light

brown solid. This material was taken up in benzene (8 mL) and 3-pentanone (0.10 mL,

0.94 mmol) and p-toluenesulfonic acid monohydrate (18 mg, 0.094 mmol) were added.

The resultant solution was then heated at reflux in a Dean-Stark trap for 16 h. The

reaction mixture was then allowed to cool to room temperature and potassium carbonate

(50 mg) was added. The reaction mixture was filtered, the filter-cake was washed with

dichloromethane (10 mL) and the combined filtrates were concentrated in vacuo to afford

the crude product as a dark brown oil. Flash chromatography using hexanes:ethyl acetate

(2: 1) as the eluant afforded the title compound (+)-334 (164 mg, 8 1%) as a colourless oil

which crystallized upon standing. [a]: + 78 (c 0.72, chloroform). The spectroscopic

data for this compound was found to be identical in every respect to the material prepared

using Method A. The enantiomeric purity of this material was determined to be 90% ee

by analytical chiral HPLC.

To a stirred solution of nickel(I1) chloride hexahydrate (135 mg, 0.570 mmol) and

triphenylphosphine (597 mg, 2.27 mmol) in anhydrous, degassed dimethylformamide (2

mL) was added zinc dust (<lo microns, 48 mg, 0.73 mmol) and the resultant suspension

was heated at 60 OC for 1 h. A solution of the acetal (+)-334 (150 mg, 0.560 mmol) in

anhydrous, degassed dimethylformamide (2 mL) was then added via a cannula and

resultant mixture was heated at 60 OC for 4 h. The reaction mixture was then allowed to

cool to room temperature and was poured into an aqueous solution of ammonium

hydroxide (10% wlw, 50 mL). The resultant mixture was extracted with dichloromethane

(3 x 15 mL). The combined organic extracts were dried over anhydrous magnesium


using hexanes:ethyl acetate (2: 1) afforded the title compound (+)-333 (1 09 mg, 84%) as a

white crystalline solid. The enantiomeric purity of this material was determined to be

>99% ee by analytical chiral HPLC using a Daicel Chiracel OD column

[hexanes:isopropanol (60:40), flow rate at 0.5 mL/min, detection at A = 220 nm; t = 23.59

min]. The enantiomeric ligand (-)-333 was also prepared from the acetal (-)-334 (53%

yield, unoptimized). The enantiomeric purity of this ligand was also determined to be

>99% ee by analytical chiral HPLC using a Daicel Chiracel OD column

[hexanes:isopropanol(60:40), flow rate at 0.5 mWmin, detection at A = 220 nm; t = 17.26

min]. Ligand (+)-333: M.p. 220-221 "C, hexaneslethyl acetate; [a] + 154 (c 0.50,

chloroform); 'H NMR (CDC13) 60.58 (6H, t, J = 7.6 Hz, CH2CH3), 0.98 (6H, t, J = 7.6

Hz, CH2CH3), 1.47-1.55 (4H, m, CH2CH3), 1.73 (4H, q, J = 7.6 Hz, CH2CH3), 2.32 (6H,

s, ArCH3), 3.07-3.1 1 (4H, m, ArCH2), 5.02-5.08 (2H, m, HCO), 5.53 (2H, d, J = 5.8 Hz,

HCO), 8.30 (2H, s, ArH); I3c NMR (CDC13) 67.8, 8.8, 19.0,29.9,30.5, 34.9, 78.0, 84.0,

115.71, 122.6, 134.1, 145.4, 157.1, 160.0;IR(KBr)2971,2937, 1746, 1591, 1463, 1434,

1376, 1307, 1202, 1168, 1135, 1080, 1060, 1009, 974, 932, 841, 730 cm-'; MS (CI) m/z

(rel. intensity) 465 (M + H, 59) 123 (100); FAB HRMS Calcd. for C28H36N204:

464.2675. Found: 464.2675. Anal. Calcd. for C28H36N204: C, 72.39; H, 7.81; N, 6.03.

Found: C, 72.28; H, 7.96; N, 5.77.

A mixture of cyclohexanone (50.0 g, 509 mmol), ethyl acetoacetate (66.3 g, 509

mmol) and ammonium acetate (39.2 g, 509 mmol) was heated at reflux for 16 h. The

reaction mixture was then allowed to cool to room temperature and was diluted with

hexanes (50 mL) which caused product to precipitate from the reaction mixture. The

product was isolated by filtration, was washed with hexanes (50 mL) and then

recrystallized from ethanol (100 mL) to afford the title compound 347 (15.0 g, 18%) as a

yellow crystalline solid. M.p. 25 1-252 "C, ethanol (lit.ll6 252-253 "C, ethanol); 'H NMR

(CDC13) 6 1.71-1.80 (4H, m, 2 x ArCH2CH2), 2.10 (3H, s, CH3), 2.34-2.42 (2H, m,

ArCH2), 2.62-2.71 (2H, m, ArCH2), 6.25 (lH, s, ArH); 13c NMR (CDC13) 6 19.8, 21.7,

22.7, 23.9, 27.3, 114.8, 116.3, 142.5, 153.9, 164.5; IR (KBr) 3426, 1649, 1538, 1457,

1203,925, 852 cm-'; MS (CI) m/z (rel. intensity) 164 (M + H, 100)

To phenylphosphonic dichloride (8.0 mL, 56 mmol) was added the pyridine-2-01

347 (4.00 g, 24.5 mmol) and the resultant solution was heated in an oil bath at 160 OC for

16 h. The reaction mixture was then allowed to cool to room temperature and water (15

mL) was added dropwise (CAUTION). The acidic reaction mixture was then diluted with

an additional quantity of water (50 mL), was neutralized by the careful addition of

potassium carbonate (- 6 g) and extracted with chloroform (3 x 25 mL). The combined

organic extracts were washed with water (30 mL), dried over anhydrous magnesium


using chloroform as the eluant afforded the title compound 348 (3.70 g, 84%) as a light

1 yellow oil. H NMR (CDC13) 6 1.78-1.88 (4H, m, 2 x ArCH2CH2), 2.19 (3H, s, CH3),

2.54-2.62 (2H, m, ArCHz), 2.83-2.92 (2H, m, ArCH2), 6.95 (lH, s, Arm; 13c NMR

(CDC13) 6 19.0, 22.7, 22.7, 25.6, 32.9, 122.4, 130.1, 149.3, 158.0; IR (neat) 2937, 2384,

1578, 1556, 1445, 1313, 1270, 11 10, 1093, 897 cm-'; MS (CI) m/! (rel. intensity) 182 (M

+ H, 100); Anal. Calcd. for CIOH12C1N: C, 66.12; H, 6.66; N, 7.71. Found: C, 66.14; H,

6.72; N, 7.69.

349

OAc

To a stirred solution of the chloropyridine 348 (2.70 g, 14.9 mmol) in glacial


mL, 69 mmol) and the resultant mixture was heated at 80 OC for 16 h. The reaction

mixture was then allowed to cool to room temperature and following concentration in

vacuo was diluted with water (100 mL). The resultant slightly acidic solution was

neutralized by the careful addition of potassium carbonate (-1.0 g) and then was

extracted with chloroform (3 x 30 mL). The combined organic extracts were washed

with water (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated in

vacuo to afford the corresponding pyridine-N-oxide (2.85 g, 97%) as a white crystalline

solid. This material was taken up in acetic anhydride (20 mL) and the resultant

suspension was heated slowly to 100 OC over the course of 1 h and then held at this

temperature for 4 h. The resultant mixture was allowed to cool to room temperature and

was then concentrated in vacuo to afford the crude product. Flash chromatography using

hexanes:ether (1:l) as the eluant afforded the title compound 349 (2.80 g, 77%) as a

colourless oil. 'H NMR (CDC13) 8 1.79-1.99 (4H, m, 2 x ArCH2CH2), 2.10 (3H, s,

OAc), 2.22 (3H, s, CH3), 2.45-2.78 (2H, m, ArCH2), 5.83 (IH, apparent t, J = 3.9 Hz,

ArCHOAc), 7.08 (1 H, s, ArH); 13c NMR (CDC13) 6 17.9, 19.0, 22.3, 25.3, 28.4, 7 1.1,

124.9, 131.7, 149.8, 153.2, 170.3; IR (neat) 2358, 2339, 1757, 1650, 1557, 1513, 1369,

1206, 1075 cm-'; MS (CI) m/z (rel. intensity) 240 (M + H, loo), 212 (43), 180 (18);

Anal. Calcd. for Cl2Hl4C1NO2: C, 60.13; H, 5.89; N, 5.84. Found: C, 59.80; H, 5.97; N,

To a stirred solution of the acetate 349 (2.00 g, 8.34 mmol) in a mixture of

tetrahydrofuran and water (3: 1, 20 mL) was added lithium hydroxide monohydrate (1.75

g, 41.7 mmol) and the resultant solution was stirred at room temperature for 5 h. The

reaction mixture was then diluted with ether (100 mL) and was washed with water (3 x

30 mL). The organic layer was dned over anhydrous magnesium sulfate and

concentrated in vacuo to afford the corresponding alcohol 350 (1.62 g, 98%) as a light

brown crystalline solid. To this material, polyphosphoric acid (1 1 g) was added and the

resultant mixture was heated at 120 OC for 30 min. The hot reaction mixture was then

poured onto crushed ice (-250 mL) and the resultant acidic solution was basified by the

addition of an aqueous solution of potassium hydroxide (20% wlw, 75 mL). The resultant

mixture then was extracted with dichloromethane (3 x 40 mL) and the combined organic

extracts were washed with water (30 mL), dried over anhydrous magnesium sulfate and


hexanes:ether (1: 1) as the eluant afforded the title compound 345 (1.24 g, 83% over two

1 steps) as a light yellow oil. H NMR (CDC13) 6 2.23 (3H, s, CH3), 2.33-2.43 (2H, m,

ArCH2CH2), 2.78 (2H, apparent t, J = 8.5 Hz, ArCH2), 6.28-6.34 (lH, m, ArCHCH), 6.54

(1 H, dt, J = 3.8, 1.9 Hz, ArCH), 6.93 (lH, s, ArH); 13c NMR (CDC13) 6 18.8, 22.5, 22.7,

123.4, 128.1, 129.0, 134.4, 147.2, 148.3, 153.2; IR (neat) 2378, 2349, 1571, 1554, 1442,

1336, 1270, 1114, 1088, 901 cm-'; MS (CI) m/! (rel. intensity) 180 (M + H, 100); Anal.

Calcd. for CloHloCIN: C, 66.86; H, 5.61; N, 7.80. Found: C, 66.57; H, 5.61; N, 7.69.

8.5.8. 2-Chloro-5,6,7,8-tetrahydro-4-methyl-quinoline-7,8-diol 3-Pentanone Acetal

(344)

To a stirred solution of the chloropyridine 345 (340 mg, 1.89 mmol) in tert-

butano1:water ( l : l , 18 mL) at 0 OC was added AD-mix-P(2.63 g) in one portion and the

resultant orange suspension was stirred at 0 OC for 12 h. Sodium sulfite (1.25 g) was then

added to the reaction mixture. After an additional 30 min, brine (50 mL) was added and

the reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic

extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to

afford the crude diol (347 mg, 86%) as a pale beige solid. This material was taken up in

anhydrous benzene (10 mL) and 3-pentanone (0.25 mL, 2.4 mmol) and p-toluensulfonic

acid monohydrate (45 mg, 0.24 mmol) were added. The resultant solution was heated in

a Dean-Stark trap at reflux for 16 h. The reaction mixture was then allowed to cool to

room temperature and potassium carbonate (60 mg) was added. The reaction mixture

was filtered, the filter-cake was washed with dichloromethane (10 mL) and the combined

filtrates were concentrated in vacuo to afford the crude product as a dark brown oil.

Flash chromatography using hexanes:ethyl acetate (2:l) as the eluant afforded the title

compound (+)-344 (420 mg, 79%, over two steps) as a colourless oil. The enantiomeric

purity of this material was determined to be 5% ee by analytical chiral HPLC using a

Daicel Chiracel OD column [hexanes:isopropanol (96:4), flow rate at 0.5 mL/min,

detection at A = 220 nm; MAJOR = 16.24 min, MINOR = 17.95 min]. 'H NMR (CDC13) 6

0.69(3H, t, J = 7 . 1 Hz, CH2CH3),0.95 (3H, t, J=7.2Hz,CH2CH3), 1.57 (2H,q, J = 7 . 4

Hz, CH2CH3), 1.72 (2H, q, J = 7.5 Hz, CH2CH3), 2.17-2.32 (5H, m, ArCH3 and

ArCH2CH2), 2.53-2.64 (lH, m, ArCHH), 2.68-2.82 (lH, m, ArCHH), 4.67 (lH, m,

HCO), 5.13 (lH, m, HCO), 7.07 (IH, s, ArH); 13c NMR (CDC13) 6 7.7, 8.9, 19.2, 19.8,

27.1, 29.0, 29.2, 73.3, 75.8, 112.6, 124.5, 131.5, 148.6, 154.2; IR (neat) 2971, 1582,

1447, 1271, 1196, 1133, 1080, 981, 893 cm-I; MS (CI) m/z (rel. intensity) 282 (M + H,

100); Anal. Calcd. for C15H20ClN02: C, 63.94; H, 7.15; N, 4.97. Found: C, 63.87; H,

7.20; N, 4.76.

8.5.9. General Procedure for Copper(1)-Catalyzed Enantioselective Cyclopropanation

Reactions of Alkenes (353a-e) with Diazoesters (354a-c)

4 N2 354a-c 1.25 mol % Cu(OTQ2,

1.5 mol % L* [(+)-333 or (-)-3331 1.5 mol % PhNHNH2, CH2CI2,

+ co2R3 room temperature, 15.5 h - R2//l 355a-g

R2 R ' + R' 353a-e

To a stirred solution of copper(I1) triflate (9.0 mg, 25 pmol) in anhydrous

dichloromethane (3 mL) was added ligand (+)-333 [or (-)-3331 (13.9 mg, 29.9 pmol) and

the resultant solution was stirred at room temperature for 30 min. Phenylhydrazine (3.0

pL, 30 pmol) and the alkene 353a-e (styrene, p-methoxystyrene, p-fluorostyrene, 4-

phenylbut- 1 -ene or 1 , 1 -diphenylethene, 4.37 mmol) were then added. A solution of the

diazoester 354a-c (ethyl, benzyl or tert-butyl diazoacetate, 2.00 mmol) in

dichloromethane (3 mL) was then added over the course of -3 h via a syringe pump.

After the addition was complete, the reaction was stirred for an additional 12 h. The

reaction mixture was then concentrated in vacuo to afford the crude product. The ratios

of the trans- and cis-isomers of the cyclopropane reaction products were then determined

by 'H NMR spectroscopy. Flash chromatography using petroleum ether:ethyl acetate

(96:4) as the eluant afforded the pure trans-cyclopropanes 355a-g and the corresponding

cis-cyclopropanes. The enantiomeric purities of the major trans-isomers of the

cyclopropane reaction products 355a-g were determined following reduction with lithium

aluminum hydride.

8.5.10. (1R,2R)-trans-2-Phenyl-cyclopropane-1-carbolic Acid Ethyl Ester (355a)

C02Et

Combined yield of trans- and cis-isomers (282 mg, 74%, 82:18) as colourless

oils. [a] - 231 (c 0.94, chloroform). The spectroscopic data for this compound was

identical to that reported in section 8.2.20. Analytical chiral HPLC analysis of the


(90:10), flow rate at 0.5 mLImin, detection at A = 220 nm, ~ M I ~ O K = 15.4 min, ~ M ~ T O ~ =

25.2 min, 82% eel.

8.5.1 1. (lR,2R)-trans-2-Phenyl-cyclopropane-1-carboxylic Acid Benzyl Ester (355b)

C02Bn

355b Ph

Combined yield of trans- and cis-isomers (247 mg, 49%, 92:8) as colourless oils.

[a] - 264 (c 0.65, chloroform); 'H NMR (CDC13) S 1.36 (lH, m, CHH), 1.67 (lH, m,

2.00 (lH, m, CHCOzBn), 2.59 (IH, m, CHPh), 5.18 (lH, s, OCHH), 5.19 (lH, s,

OCHH), 7.08-7.14 (2H, m, Arm, 7.18-7.32 (3H, m, ArH), 7.33-7.43 (5H, m, ArH); I3c

NMR (CDC13) S 17.4, 24.2, 26.5, 66.7, 126.3, 126.6, 128.3, 128.6, 128.7, 136.1, 140.0,

173.4; IR (neat) 1720, 1603, 1498, 1457, 1407, 1338, 1325, 1168, 1030, 973, 934, 851,

752, 699 cm-'; MS (CI) m/z (rel. intensity) 253 (M + H, 77), 91 (100). Analytical chiral

HPLC analysis of the corresponding primary alcohol using a Daicel Chiracel OD column

[hexanes:isopropanol(90: lo), flow rate at 0.5 mLImin, detection at A = 220 nm, MI NO^ =

15.4 min, t ~ . t , ~ o ~ = 25.2 min, 84% eel.

8.5.12. (lR,2R)-trans-2-Phenyl-cyclopropane-1-carbolic Acid tert-Butyl Esters

(355c) and (ent-355c)


[a] ZP - 237 (c 0.92, chloroform). The spectroscopic data for this compound was identical

to that reported in 8.2.21. Analytical chiral HPLC analysis of the corresponding primary

alcohol using a Daicel Chiracel OD column [hexanes:isopropanol (90: lo), flow rate at

0.5 mLImin, detection at il = 220 nm, MINOR = 15.4 min, tMkTo~ = 25.2 min, 92% eel.

The above procedure was also carried out, on a smaller scale, using ligand (-)-333 to

afford the cyclopropanes ent-355c (181 mg, 68%, 96:4) as colourless oils. Analytical

chiral HPLC analysis of the corresponding primary alcohol using a Daicel Chiracel OD

column [hexanes:isopropanol (90: lo), flow rate at 0.5 mLImin, detection at il = 220 nm,

MAJOR = 15.4 min, t ~ m o ~ = 25.2 min, 93% eel.

8.5.13. (l~2R)-trans-2-(4-Methoxyphenyl)-cyclopropane-l-carbolic Acid tert-Butyl

Ester (355d)


[a] - 189 (c 0.75, chloroform); 'H NMR (CDC13) 6 1.18 (lH, m, CHH), 1.45-1 S 2

(lOH, m, t-Bu and CKH), 1.75 (lH, m, CHC02t-Bu), 2.40 (lH, m, CHPh), 3.78 (3H, s,

0CH3), 6.80-6.84 (2H, m, ArH), 7.01-7.04 (2H, m, ArH); 13c NMR (CDC13) 6 17.1,

25.3, 25.5, 28.5, 55.7, 80.8, 114.2, 127.6, 132.8, 158.5, 173.1; IR (neat) 2978, 2934,

1717, 1612, 1518, 1457, 1403, 1370, 1342, 1293, 1252, 1153, 1025, 845, 825, 813, 748

cm-'; MS (CI) m/z (rel. intensity) 249 (M + H, 6), 193 (100). Analytical chiral HPLC

analysis of the corresponding primary alcohol using a Daicel Chiracel OD column

[hexanes:isopropanol (90: lo), flow rate at 0.5 mL/min, detection at A = 220 nm, ?MINOR =

2 1.2 min, t ~ ~ o ~ = 24.0 min, 7 1 % eel.

8.5.14. (lR,2R)-trans-2-(4-FIrcorophenyl)-cyclopropane-l-carboxylic Acid tert-Butyl

Ester (355e)


[a] - 182 (c 0.64, chloroform); 'H NMR (CDC13) 6 1.18 (lH, m, CHH), 1.47 (9H, s, t-

Bu), 1.48-1.53 (lH, m, CHH), 1.75-1.80 (lH, m, CHC02t-Bu), 2.42 (lH, m, CHPh),

6.93-6.99 (2H, m, ArH), 7.02-7.08 (2H, m, ArH); 13c NMR (CDC13) 6 17.3, 25.3, 25.4,

28.5, 81.0, 115.5, 115.6, 127.9, 128.0, 134.9, 136.4, 162.8, 164.8, 172.8; IR (neat) 2980,

1719, 16708, 1515, 1457, 1398, 1368, 1334, 1312, 1218, 1152, 980, 846, 826, 767, 745

cm-'; MS (CI) m/z (rel. intensity) 237 (M + H, 19), 181 (100); Anal. Calcd. for

Cl4HI7FO2: C, 71.16; H, 7.25. Found: C, 70.97; H, 7.07. Analytical chiral HPLC analysis

of the corresponding primary alcohol using a Daicel Chiracel OD column

[hexanes:isopropanol(90: lo), flow rate at 0.5 mL/min, detection at A = 220 nm, =

14.4 min, t ~ ~ j o ~ = 16.2 min, 99% eel.

8.5.15. (lR,2R)-trans-2-(2 '-Pheny1ethyl)-cyclopropane-1-carboxylic Acid tert-Butyl

Ester (355f)


[a]: - 41 (c 0.50, chloroform); 'H NMR (CDC13) 60.56 (lH, ddd, J = 10.3, 6.3, 3.9 Hz,

CHH), 1.00-1.04 (lH, m, CHH), 1.18-1.28 (2H, m, PhCH2CHHCH), 1.38 (9H, s, t-Bu),

1.50-1.57 (2H, m, PhCH2CHH and CHC02t-Bu), 2.63-2.68 (2H, m, PhCH2), 7.09-7.15

(3H, m, ArH), 7.18-7.24 (2H, m, Arm; 13c NMR (CDC13) 6 15.5, 21.6, 22.3, 28.5, 35.3,

35.9, 80.3, 126.2, 128.7, 128.8, 142.1, 174.0; IR (neat) 2979, 293 1, 2858, 1724, 1603,

1497, 1455, 1404, 1368, 1258, 1214, 1146, 1079, 978, 848, 748, 699 cm-'; MS (CI) m/z

(rel. intensity) 247 (M + H, 49), 192 (14), 191 (100); Anal. Calcd. for Cl6H22O2: C,

78.01; H, 9.00; Found: C, 77.78; H, 9.30. Analytical chiral HPLC analysis of the


(90:10), flow rate at 0.5 mL/min, detection at A = 220 nm, t ~ n \ l o ~ = 16.2 min, ~MMOR =

19.8 min, 83% eel.

8.5.1 6. (1 R)-2,2-Diphenyl-cyclopropane-1 -carboxyi acid tert-Butyl Ester (355g)

Yield (477 mg, 81%) as a colourless oil. [a] - 165 (c 0.25, chloroform); 'H

NMR (CDC13) 6 1.21 (9H, s, t-Bu), 1.49-1.53 (lH, m, CHH), 2.09-2.13 (1H, m, CHH),

2.46 (lH, dd, J = 7.8, 5.9 Hz, CHC02t-Bu), 7.14-7.22 (2H, m, ArH), 7.23-7.29 (6H, m,

ArH), 7.35-7.38 (2H, m, A H ) ; 13c NMR (CDCls) 620.2, 28.0, 30.2, 39.6, 80.5, 126.5,

127.0, 127.7, 128.3, 128.5, 130.2, 140.4, 145.3, 169.8; IR (neat) 2977,2934, 1719, 1662,

1601, 1496, 1448, 1390, 1367, 1293, 1250, 1150, 1028, 972, 847, 781, 747, 703 cm-';

MS (CI) m/z (rel. intensity) 295 (M + H, 6), 239 (loo), 183 (16). Analytical chiral HPLC

analysis of the corresponding primary alcohol using a Daicel Chiracel OD column

[hexanes:isopropanol (90: lo), flow rate at 0.5 mL/min, detection at A = 220 nm, t ~ m o ~ =

22.6 min, t ~ ~ j o ~ = 18.8 min, 72% eel.

8.5.17. General Procedure for the Copper(I0-Catalyzed Asymmetric Friedel-Crafts

Reactions using Ligand [(+)-3331

10 mol % Cu(OTf)2, R~

10 rnol % L* (+)-333, W 3 + F3C co2R4

Et20, 0 "C, 16 h

N R2

To a flame-dried Schlenk tube was added copper( 11) trifluoromethanesulfonate

(3.1 mg, 8.6 p o l ) , ligand (+)-333 (4.1 mg, 8.8 p o l ) and ether (1.5 mL). The resultant

solution was stirred at room temperature for 1 h. The catalyst solution was then cooled to

0 OC and the appropriate indole 367a-f (94 p o l ) and the ethyl or methyl ester of 3,3,3-

trifluoropyruvic acid 368a,b (86 p o l ) were added. The Schlenk tube was then sealed

and the reaction mixture was stirred at 0 OC for 16 h. The resultant mixture was then


hexanes:ether (1 : 1) as the eluant afforded the desired substituted indoles 369a-g.

8.5.18. (2S)-3,3,3-Trifluoro-2-hydroxy-(indole-3-y-propionic Acid Ethyl Ester (369a)

Indole 367a (1 1.0 mg, 94 pmol) was reacted with ethyl 3,3,3-trifluoropyruvate

368a (1 1 pL, 86 pmol) according to the general procedure to afford the title compound

369a (1 7 mg, 68%) as a colourless oil. [a] + 1 1.3 (c 1.01, chloroform) [lit.'68 [a] +

12.3 (c 1.91, chloroform), 83% eel; 'H NMR (CDC13) 61.35 (3H, t, J = 7.1 Hz,

C02CH2CH3), 4.33-4.39 (lH, m, C02CMHCH3), 4.42-4.50 (lH, m, C02CHHCH3), 7.14-

7.19 (lH, m, ArH), 7.21-7.26 (lH, m, ArH), 7.39 (IH, d, J = 8.1 Hz, ArH), 7.49 (lH, d, J

= 2.6 Hz, ArH), 7.91 (lH, d, J = 8.1 Hz, ArH), 8.27 (IH, broad s, NH); 13c NMR

(acetone-D6) 6 15.2, 64.6, 79.2 (q, 2 ~ C - ~ = 31 HZ), 110.7, 113.5, 121.4, 122.9, 123.7,

126.3 (q, 'JC+ = 285 Hz), 126.8, 127.4, 138.8, 170.3; IR (KBr) 3417 (broad), 1741, 1462,

1372, 13 10, 1229, 1 176, 1097, 1008, 909, 858, 75 1 cm-'; MS (CI) m/z (rel. intensity) 270

(52), 171 (100). Analytical chiral HPLC analysis using a Daicel Chiracel OD column

[hexanes:isopropanol (90: lo), flow rate at 0.5 mllmin, detection at A = 220 nm, MIN NO^ =

32.5 min, ~ M A J ~ R = 37.1 min, 74% eel.

8.5.19. (2S)-3,3,3-Trifluoro-2-hydroxy-(indole-3-y-propionic Acid Methyl Ester

Indole 367a (1 1.0 mg, 94 pmol) was reacted with methyl 3,3,3-trifluoropyruvate

368b (8.7 pL, 86 pmol) according to the general procedure to afford the title compound

369b (18 mg, 77%) as a colourless oil. [a]: - 24.1 (c 0.99, chloroform); 'H NMR

(CDC13) 63.94 (3H, s, C02CH3), 4.35 (lH, broad s, OH), 7.14-7.20 (lH, m, ArH), 7.21-

7.25 (lH, m, ArH), 7.36-7.41 (lH, m, ArH), 7.44-7.48 (lH, m, ArH), 7.87 (lH, d, J = 8.0

Hz, ArH), 8.29 (lH, broad s, NH); "C NMR (acetone-D6) 658.0, 82.5 (q, 2 ~ C - F = 31 HZ),

113.9, 116.8, 124.9, 126.0, 127.1, 129.5 (q, 'JC-~ = 286 Hz), 130.1, 130.7, 142.0, 174.2;

IR (neat) 3414 (broad), 3331 (broad), 1750, 1461, 1438, 1341, 1299, 1261, 1233, 1173,

11 18, 1102, 1080, 999, 907, 753 cm-'; MS (CI) m/z (rel. intensity) 273 (M + H, 12), 256

(100); Anal. Calcd. for CI2HI0F3NO3: C, 52.75; H, 3.69; N, 5.13. Found: C, 52.90; H,

3.69; N, 5.06. Analytical chiral HPLC analysis using a Daicel Chiracel OD column

[hexanes:isopropanol (90: lo), flow rate at 0.5 mLImin, detection at A = 220 nm, tM1~oR =

44.2 min, t ~ ~ o ~ = 45.8 min, 90% eel.

8.5.20. (2s)-3,3,3- Trifluoro-2-hydroxy-(2-methylindole-3-y-propionic Acid Methyl

Ester (369c)

2-Methylindole 36713 (12.4 mg, 94 pmol) was reacted with methyl 3,3,3-

trifluoropyruvate 36813 (8.7 pL, 86 pmol) according to the general procedure to afford the

title compound 369c (20 mg, 79%) as a light yellow oil. [a] + 7.1 (c 1.70, chloroform);

'H NMR (CDC13) 6 2.50 (3H, s, CH3), 2.52 (3H, s, C02CH3), 7.07-7.19 (2H, m, ArH),

7.26-7.30 (lH, m, ArH), 7.75 (lH, d, J = 8.0 Hz, ArH), 8.03 (lH, broad s, NH); 13c

NMR (acetone-D6) 6 14.5, 54.1, 79.7 (q, 2 ~ c - ~ = 30 HZ), 105.9, 112.4, 121.3, 121.4,

122.7, 126.9 (q, I J C - ~ = 284 Hz), 129.1, 137.0, 137.5, 170.9; IR (neat) 3401 (broad),

1741, 1694, 1461, 1438, 1291, 1183, 1029, 748 cm-'; MS (CI) m/z (rel. intensity) 287 (M

+ H, loo), 270 (50); FAB HRMS Calcd. for CI3Hl2F3NO3: 287.0769. Found: 287.0774.

Analytical chiral HPLC analysis using a Daicel Chiracel OD column

[hexanes:isopropanol(90: lo), flow rate at 0.5 mLImin, detection at A = 220 nm, MAJOR =

43.9 min, t ~ m o ~ = 63.3 min, 86% eel.

8.5.21. (2S)-3,3,3-Trifuoro-2-hydroxy-(5-methoxyindole-3-yl)-propionic Acid Methyl

Ester (369d)

5-Methoxyindole 367c (13.9 mg, 94 pmol) was reacted with methyl 3,3,3-

trifluoropyruvate 368b (8.7 pL, 86 pmol) according to the general procedure to afford the

title compound 369d (1 8 mg, 69%) as a colourless oil. [a] - 1.7 (c 1 .3O, chloroform);

1 H NMR (CDCl3) 63.84 (3H, s, OCH3), 3.92 (3H, s, C02CH3), 6.86-6.91 (lH, m, ArH),

7.18 (lH, d, J = 8.9 Hz, ArH), 7.30-7.34 (2H, m, ArH), 8.33 (lH, broad s, NH); 13c

NMR (acetone-D6) 6 54.8, 56.8, 79.2 (q, 2 ~ C - F = 31 HZ), 104.4, 114.2, 114.9, 124.9,

127.3, 127.7 (q, 'JC-F = 288 Hz), 127.7, 127.9, 133.9, 170.8; IR (neat) 3409 (broad),

1748, 1692,1628, 1583, 1488, 1441, 1294, 1217, 1178, 1113, 1026, 1000,906,794 cm-';

MS (CI) m/z (rel. intensity) 303 (M + H, 100), 286 (41), 244 (16), 174 (24), 147 (67);

FAB HRMS Calcd. for C13H12F3N04: 303 .O7 18. Found: 303 .O7 16. Analytical chiral

HPLC analysis using a Daicel Chiracel OD column [hexanes:isopropanol (90:10), flow

rate at 0.5 mL/min, detection at A = 220 nm, t ~ m o ~ = 61.5 min, MAJOR = 72.5 min, 72%

eel.

8.5.22. (2s)-3,3,3- Trifuoro-2-hydroxy-(5-nitroindole-3-yl)-propionic Acid Methyl

Ester (369e)

5-Nitroindole 367d (15.3 mg, 94 pmol) was reacted with methyl 3,3,3-


title compound 369e (21 mg, 75%) as a yellow crystalline solid. M.p. 139-140 "C,

hexaneslether; [a] - 0.5 (c 1.00, chloroform); 'H NMR (CDC13) 6 4.01 (3H, s,

C02CH3), 4.27 (lH, broad s, OH), 7.45 (IH, d, J = 9.0 Hz, ArH), 7.67-7.70 (lH, m,

ArH), 8.16 (lH, dd, J = 9.0, 2.2 Hz, ArH), 8.74 (lH, broad s, NH), 8.92-8.95 (IH, m,

Am; 13c NMR (acetone-&) 6 55.2, 79.2 (q, 'JC-F = 30 HZ), 113.0, 114.1, 119.1,

120.1,125.8 (q, 'JC-F = 285 Hz), 126.8, 130.7, 141.7, 143.9, 170.2; IR (KBr) 3400

(broad), 3373 (broad), 1754, 1521, 1473, 1339, 1303, 1224, 1198, 1169, 1108, 1053,989,

941, 660 cm-'; MS (CI) m/z (rel. intensity) 319 (M + H, loo), 302 (33), 259 (51); Anal.

Calcd. for C,2H9F3N2O5: C, 45.29; H, 2.85; N, 8.80. Found: C, 45.02; H, 3.06; N, 8.51.

1 H NMR analysis of the reaction product in the presence of the chiral shift reagent

Eu(hfc)3 indicated a 3.9: 1 .O ratio of enantiomers, 60% ee.

8.5.23. (2s)-3,3,3- Trifluoro-2-hydroxy-(1 -methylindole-3-y-propioi Acid Methyl

Ester (369f)

I-Methylindole 367e (12.3 mg, 94 pmol) was reacted with methyl 3,3,3-


title compound 369f (18 mg, 74%) as a colourless oil. 'H NMR (CDC13) 63.80 (3H, s,

NCH3), 3.94 (3H, s, C02CH3), 7.13-7.19 (IH, m, ArH), 7.24-7.30 (IH, m, ArH), 7.31-

7.35 (2H, m, ArH), 7.82-7.87 (lH, d, J = 8.2 Hz, ArH); 13c NMR (acetone-&) 634.1,

54.8, 79.1 (q, 2 ~ ~ - ~ = 31 HZ), 109.5, 111.6, 121.6, 122.9, 123.8, 126.2 (q, l J C - ~ = 286 Hz),

127.8, 130.9, 139.2, 170.8; IR (neat) 3488 (broad), 1742, 1544, 1477, 1466, 1296, 1173,

1135, 745 cm-'; MS (CI) m/z (rel. intensity) 288 (M + H, 46), 270 (100); FAB HRMS

Calcd. for C13H12F3N03: 287.0769. Found: 287.0769. Analytical chiral HPLC analysis

using a Daicel Chiracel OD column [hexanes:isopropanol (90:10), flow rate at 0.5

mLImin, detection at /Z = 220 nm, t M m o ~ = 26.2 min, tMkloR = 37.1 min, 18% eel.

8.5.24. (2S)-3,3,3-Trifuoro-2-hydroxy-(l-methyl-2-phenyZindole-3-y-propionic Acid

Methyl Ester (3698)

1-Methyl-2-phenylindole 369f (19.5 mg, 94 pmol) was reacted with methyl 3,3,3-


1 title compound 3698 (20 mg, 65%) as a colourless oil. H NMR (CDC13) 63.26 (3H, s,

(lH, d, J = 8.1 Hz, ArH); 13c NMR (acetone-&) 653.5, 79.7 (q, 2 ~ c + = 30 HZ), 111.4,

121.7, 123.9, 124.3, 126.5 (q, 'JC-F = 285 Hz), 129.7, 129.9, 130.9, 132.7, 133.0, 133.7,

138.4, 141.2, 169.7; IR (neat) 3445 (broad), 1736, 1467, 1442, 1294, 1238, 1188, 1 106,

1069, 984, 748 cm-'; MS (CI) m/z (rel. intensity) 364 (M + H, 93), 346 (100); FAB

HRMS Calcd. for Cl9Hl6F3No3: 363.1082. Found: 363.1083. Analytical chiral HPLC

analysis using a Daicel Chiracel OD column [hexanes:isopropanol(96:4), flow rate at 0.5

mLlmin, detection at A = 245 nm, MINOR = 25.6 min, t ~ ~ j o ~ = 26.4 min, 18% eel.

8.5.25. (4S)-4-(Indole-3-yI)-4-phenyl-2-oxo-butanoic Acid Methyl Ester ( 3 7 0 ) ' ~ ~

10 mol % Cu(OTfh, H P h 0 10 mol % L* (+)-333,

H 0 Et20, -78 "C, 16 h *e C02Me

N 97% N

H H

367a 365 370

To a flame-dried Schlenk tube was added copper(I1) trifluoromethanesulfonate

(3.1 mg, 8.6 pmol), ligand (+)-333 (4.1 mg, 8.8 pmol) and ether (2.0 mL) and the

resultant solution was stirred at room temperature for 1 h. The catalyst solution was then

cooled to -78 "C and indole 367a (10.0 mg, 86 pmol) and (3E)-2-0x0-4-phenyl-3-

butenoic acid methyl ester 3 6 ~ ~ ~ ~ (16.4 mg, 86 pmol) were then added. The resultant

heterogeneous mixture was stirred at -78 "C for 16 h. The reaction mixture was then

allowed to warm to room temperature and was filtered through a pad of silica gel using

ether as the eluant. The filtrate was concentrated in vacuo to afford the desired product

as the corresponding en01 tautomer in pure form. The en01 was smoothly converted to

the desired ketone on stirring in methanol (5 mL) at room temperature for 2 h. On

concentration in vacuo, the title compound 370 (25 mg, 97%) was isolated as a white

crystalline solid. M.p. 93-94 "C, methanol (lit.169 98 "C, etherlpentane); [a] + 14.1 (c

1.00, chloroform) [lit.169 [a] - 23.9 (c 1.00, chloroform), 99.5% eel; 'H NMR (CDC13)

63.6 (IH, dd, J = 17.0, 8.0 Hz, CHH), 3.69 (lH, dd, J = 17.0, 7.1 Hz, CHH), 3.77 (3H, s,

C02CH3), 4.93 (lH, t, J = 7.5 Hz, PhCH), 6.99-7.46 (lOH, m, ArH), 7.99 (lH, broad s,

NH); 13c NMR (CDC13) 6 38.9, 45.9, 53.2, 111.3, 116.5, 119.7, 120.2, 122.3, 126.7,

(1 83) Dujardin, G.; Leconte, S.; Benard, A.; Brown, E. A Straightforward Route to E-y-Aryl-a-oxobutenoic

Esters by One-Step Acid-Catalysed Crotonisation of Pyruvates. Synlett 2001, 147.

128.3, 136.2, 143.3, 161.1; IR (KBr) 3447 (broad), 1744, 1699, 1490, 1456, 1438, 1376,

1240, 1091, 1071, 768, 747 cm-'; MS (CI) m/z (rel. intensity) 290 (25), 191 (loo), 118

(34). The enantiomeric purity of the reaction product was determined by comparison of

the optical rotation with a literature value, 59% ee.'69

Carboxylate (372)170

10 mol % Cu(OTfh, 10 mol % L* (+)-333,

PhNMe2, PhMe, H 0 0 "C, 16 h

Me0 nOH + Ph"C02Me 62% Me0 Ph

37 1 365 372

To a flame-dried Schlenk tube was added copper(I1) trifluoromethanesulfonate

(9.0 mg, 25 pmol), ligand (+)-333 (13.0 mg, 28 pmol) and toluene (1.0 mL) and the

resultant solution was stirred at room temperature for 1 h. (3E)-2-0x0-4-phenyl-3-

butenoic acid methyl ester 365 (58 mg, 0.25 mmol) and N,N-dimethylaniline (3.2 pL, 25

pmol) were then added and the solution was cooled to 0 OC. 3-methoxyphenol 371 (55

pL, 0.50 mmol) was added to the resultant solution which was then stirred at 0 OC for 16

h. The reaction mixture was then concentrated in vacuo to afford the crude product.

Purification by flash chromatography using pentane:ether (5:l) as the eluant afforded the

title compound 372 (49 mg, 62%) as a colourless oil. [a] + 0.75 (c 1.00, chloroform)

[lit.l7O [a] + 1.36 (c 1.55, chloroform), 80% eel; 'H NMR (CDC13) 62.26 (lH, dd, J =

13.4, 5.5 Hz, CHH), 2.45 (lH, td, J = 2.0, 13.2 Hz, CHH), 3.75 (3H, s, C02CH3), 3.90

(3H, s, 0CH3), 4.28 (lH, dd, J = 13.2, 5.5 Hz, PhCH), 4.37 (lH, broad d, J = 2.0 Hz,

OH), 6.40-6.47 (2H, m, ArH), 6.64 (IH, d, J = 8.4 Hz, ArH), 7.23-7.38 (5H, m, ArH);

13c NMR (CDC13) S 37.1, 53.8, 55.6, 94.7, 102.0, 108.8, 118.0, 127.2, 129.0, 129.1,

130.2, 143.8, 152.4, 159.7, 170.5; IR (neat) 3450 (broad), 1750, 1621, 1581, 1504, 1442,

1256, 1161, 1123, 1032 cm-'; MS (CI) m/z (rel. intensity) 315 (M + H, 38), 265 (100).


[hexanes:isopropanol(98:2), flow rate at 0.75 mL/min, detection at A = 220 nm, =

34.4 min, MINOR = 36.7 min, 42% eel.

8.5.27. Procedure for the Preparation and Crystallization of the CuC12 Ligand [(+)-

3333 Complex

A solution of the ligand (+)-333 (12.4 mg, 26.7 pmol) and copper(I1) chloride (3.8

mg, 28 pmol) in a mixture of ethano1:dichloromethane (1: 1, 4 mL) was heated at reflux

for 6 h. The reaction mixture was then allowed to cool to room temperature and was

concentrated in vacuo to afford the crude product. This material was then taken up in

dichloromethane (2 mL) and filtered through a pad of glass wool. Ethanol (1 mL) was

then added to the filtrate and upon slow evaporation of the solvent, the title compound

(10 mg, 62%) was obtained as X-ray quality yellow crystals. M.p. >210 "C (dec.),

dichloromethane/ethanol; [a] i:, + 759, [a] ::, + 2552, [a] ::, + 1207, [a]:%, + 793 (c

0.0029, chloroform); UV-Vis A,, (chloroform) 328 (E = 19597), 3 15 (E = 20446) nm; IR

(KBr) 3433 (broad), 3044,2972,2937,2880, 1604, 1478, 1463, 1196, 1176, 1091, 1082,

929 cm-'; MS (MALDI-TOF) m/z 562 (M - Cl), 465 (M - CuC12 + H); Anal. Calcd. for

C28H36C12C~N204: C, 56.14; H, 6.06; N, 4.68. Found: C, 56.3 1; H, 6.12; N, 4.75.

8.5.28. X-Ray Crystallographic Analysis of the CuClz.Ligand [(+)-3331 Complex

A single crystal, a yellow platelet that had the dimensions 0.06 x 0.23 x 0.28 mm3,

was mounted on a glass fiber using epoxy adhesive. The data for this crystal of the

CuC12*ligand (+)-333 complex was acquired at 293 K on a Rigaku RAXIS-RAPID curved

image plate area detector with graphite monochromated Cu K a radiation. Indexing for

the crystal was performed using four, 5" oscillations that were exposed for 400 seconds.

The following data range was recorded: 4.1" < 2 6 5 144.3" and a total of 54 images were

collected. A sweep of data was then collected using w scans from 0.0" to 180.0" in 10"

steps, at x = 0.0" and 4 = 0.0". A second sweep of data was collected using w scans from

0.0" to 180.0" in 10" steps, at X = 45.0" and 4= 0.0". A final sweep of data was collected

using w scans from 0.0" to 180.0" in 10" steps, at x = 45.0" and 4 = 90.0". The exposure

rate was 100 secI0 and in each case, the crystal-to-detector distance was 127.40 mm. A

numerical absorption correction was then applied which resulted in the following

transmission range: 0.69 to 0.83. The coordinates and anisotropic displacement

parameters for the non-hydrogen atoms were then refined. Of note, hydrogen atoms were

placed in calculated positions (d C-H 0.95 A) and their coordinate shifts were linked with

those of the respective carbon atoms during refinement. Isotropic thermal parameters for

the hydrogen atoms were initially assigned proportionately to the equivalent isotropic

thermal parameters of their respective carbon atoms. Subsequently, the isotropic thermal

parameters for the hydrogen atoms were constrained to have identical shifts during

refinement. The programs used for all absorption corrections, data reduction, and

processing were from the Rigaku CiystalClear package. The structure was refined using

CRYSTALS.'~~ Complex scattering factors for neutral atoms were used in the calculation

of structure factors.'78 An ORTEP representation of the CuC12*ligand (+)-333 complex is

provided below (Figure 8.5.1 .). Crystallographic data, fractional atomic coordinates and

equivalent isotropic thermal displacement parameters, selected bond lengths, and selected

bond angles for the CuC12.1igand (+)-333 complex are listed below (Table 8.5.1 ., 8.5.2.,

8.5.3., and 8.5.4., respectively).

Figure 8.5.1. ORTEP representation of the CuC12-ligand (+)-333 complex'

(*) The thermal ellipsoids are drawn at a 25% probability level for clarity.

Table 8.5.1. Summary of Crystallographic Data for the CuC12.Ligand (+)-333 Complex

Empirical formula C28H36N2ChC~04

F W (g mol-') 599.06

Temperature (K) 293

Wavelength (Cu Ka, A) 1.54180

Crystal systems monoclinic

Space group P 21

a ( 4 8.7438(6)

b (A) 7.6589(3)

c ( 4 21.3498(9)

a (O) 90

P ("1 90.022(3)

Y ( O ) 90

z 2

u (A3> 1429.75(13)

Dcalc (g ~ m - ~ ) 1.391

28 limits (") 4-145

Reflections collected 10274

Independent reflections 346 1

Reflections observed [I = 2.50(1)] 3374

Goodness-of-fit on F 1.1741

RI , RW [I= 2.5441 0.0436,0.0553


Parameters [U(iso), (A2)] for the CuC12.Ligand (+)-333 Complex*

atom x Y z U (iso)

I Cul / -0.75010(9) / -0.0208(2) 1 -0.25004(4) 1 0.0378 1


/ H l l l / -0.2040(8) / 0.1016(9) / -0.2255(3) ) 0.061(4) /

Table 8.5.3. Bond Lengths (a) for the CuCIyLigand (+)-333 Complex

Table 8.5.4. Bond Angles (") for the CuC12.Ligand (+)-333 Complex

8.5.29. Optical Rotary Dispersion Spectrum of the Copper(II) Chloride-Ligand (+)-333

complex

The following optical rotary dispersion spectrum of the copper(I1) chloride*ligand

(+)-333 complex was recorded at 20 O C in chloroform [c 0.0029 (g per 100 mL)] (Figure

8.5.2.).

Optical Rota y Dispersion Spectrum

.I moo

293 nm. +2.3 s lo'

i t S39 om, +J.O r 10'

Y

V 332 nm,-1.2 x 10'

200 300 400 500 600 700 800

Wavelength (nm)

Figure 8.5.2. Optical rotary dispersion spectrum of the CuC12-ligand (+)-333 complex.

8.5.30. General Procedure for Copper(1)-Catalyzed Asymmetric Allylic Oxidation

Reactions of Cyclopentene [373a (n = I)], Cyclohexene [373b (n = 2)] and

Cycloheptene [373c (n = 3)] with tert-Butyl Peroxybenzoate (374): Asymmetric

Syntheses of (IS)-Cyclopent-2-enyl Benzoate [(a-3 75a (n = I)], (IS)-Cyclohex-2-enyl

Benzoate [(a-375b (n = 2)] and (IS)-Cyclohept-2-enyl Benzoate [(a-375c (n = 3)].

0 0

Ph A0,0. 'BU 374 5 mol % Cu(OTf),, 5.25 mol % L* (+)-333, 5.25 mol % PhNHNH2, acetone or MeCN, 0 "C or rt

oAPh

+ t A

To a screw-cap vial was added copper(I1) trifluoromethanesulfonate (6.3 mg, 17

pmol), the chiral 2,2'-bipyridine ligand (+)-333 (8.5 mg, 18 pmol) and the reaction

solvent (acetone or acetonitrile, 2.5 mL). The resultant solution was then stirred at room

temperature for 1 h. Phenylhydrazine (2.0 pL, 20 pmol) was then added and the reaction

mixture was stirred for an additional 5 min at room temperature. The reaction mixture

was then heated to a specific temperature (see: Table 5.9.1, Chapter 5) and the

appropriate cyclic alkene substrate was added [(I) cyclopentene 373a (n = 1) (0.15 mL,

1.7 mmol) or (2) cyclohexene 373b (n = 2) (0.18 mL, 1.8 mmol) or (3) cycloheptene

373c (n = 3) (0.20 mmol, 1.7 mmol)]. The oxidant tert-butyl peroxybenzoate 374 (67 pL,

0.35 mmol) was then added and the reaction vial was capped. The progress of the

reaction was monitored by thin-layer chromatography until the tert-butyl peroxybenzoate

had been consumed. The reaction mixture was then concentrated in vacuo to afford the


title compounds (5')-375a-c (n = 1-3).

8.5.3 1. (I S)-Cyclopent-2-en Benzoate [Q-375a]

OBz

1 H NMR (CDC13) 6 1.98-2.02 (lH, m, 0 ; 2.20-2.70 (3H, m CH2 and CHH),

5.91 -5.96 (2H, m, OCH and CH), 6.15 (1 H, apparent d, J = 4.8 Hz, CH), 7.45-7.49 (3H,

m, ArH), 8.03 (2H, dd, J = 7.7, 1.8 Hz, ArH); 1 3 c NMR (CDC13) 6 29.9, 30.9, 8 1.1,

128.8, 129.3, 129.4, 130.4, 132.7, 134.4, 137.6, 162.3; IR (neat) 3062, 1714, 1270, 1116,

1026, 7 11 cm-'; MS (CI) m/z (rel. intensity) 189 (M + H, 100). Analytical chiral HPLC

analysis using a Daicel Chiracel OD column [hexanes:isopropanol (250:1), flow rate at

0.50 mllmin, detection at iZ = 220 nm, t ~ ~ j o p , = 32.4 min, t ~ ~ ~ o p , = 43.6 min].

8.5.32. (IS)-Cyclohex-2-enyl Benzoate [Q-375bl

OBz

1 H NMR (CDC13) 6 1.65- 1.76 (lH, m, CHH), 1.78-2.21 (5H, m, 2 x CH2, CHH),

5.49-5.55 (lH, m, CHOBz), 5.80-5.87 (lH, m, CH), 5.98-6.04 (lH, m, CH), 7.40-7.66

(4H, m, ArH), 8.06 (lH, d, J = 7.3 Hz, ArH), 8.13 (lH, d, J = 7.3 Hz, ArH); 1 3 c NMR

166.4; IR (neat) 2941, 1713, 1602, 1584, 1453, 1428, 1326, 1271, 1178, 11 12, 1070,

1026, 918 cm-I; MS (CI) m/z (rel. intensity) 203 (M + H, 14), 181 (87), 159 (24), 91 (55).


[hexanes:isopropanol (250: I), flow rate at 0.50 mLImin, detection at iZ = 220 nm, t ~ ~ j o p ,

= 26.1 min, t ~ ~ ~ o p , = 29.0 min].

8.5.33. (IS)-Cyclohept-2-enyl Benzoate [(q-375~1

OBz

1 H NMR (CDC13) S 1.40-1.55 (lH, m, CHH), 1.65-1.91 (3H, m, CH2 and CHH),

1.94-2.06 (2H, m, CH2), 2.09-2.21 (lH, m, CHH), 2.21-2.31 (lH, m, CHH), 5.66 (lH,

apparent d, J = 9.9 Hz, CHOBz), 5.77-5.83 (IH, m, CH), 5.85-5.93 (lH, m, CH), 7.40-

ArH), 8.10-8.15 (1 H, m, ArH); 13c NMR (CDC13) S 26.7, 26.9, 28.7, 33.0, 74.8, 122.7,

128.4, 129.1, 129.7, 132.1, 132.9, 133.6, 166.0; IR (neat) 2930, 2856, 1717, 1602, 1584,

145 1, 1273, 1 1 13, 1070, 1026, 980 cm-'; MS (CI) m/z (rel. intensity) 123 (PhC02H + H,

33), 95 (M - PhCOO, 100); Analytical chiral HPLC analysis using a Daicel Chiracel OD

column [hexanes:isopropanol(250: l), flow rate at 0.50 mllmin, detection at A = 220 nm,

MAJOR = 19.2 min, MINOR = 23.5 min].

APPENDICES

9.1. Circular Dichroism Spectrum of the C ~ ( 2 6 7 ) ~ C u C l ~ Complex

A circular dichroism spectrum was recorded for the C~(267c)~*CuC1~ complex

(Figure 9.1.1.). The spectrum was recorded at

C ~ ( 2 6 7 c ) ~ C u C l ~ complex in 100 mL of chloroform

wavelength range of 200 to 800 nm.

Circular Dichroism Spectrum

20 -- - - - -

l

a concentration of 3.0 mg

(1.9 x 10 '~ M) and across a

400 500 600

Wavelength (nm)

Figure 9.1.1. Circular dichroism spectrum o f t h e C ~ ( 2 6 7 c ) ~ C u C l ~ complex.

9.2. Circular Dichroism Spectrum of the CuC12*ligand (+)-333 Complex

A circular dichroism spectrum was recorded for the CuCl2*ligand (+)-333

complex (Figure 9.2.1.). The spectrum was recorded at a concentration of 2.9 mg

CuC12.1igand (+)-333 complex in 100 mL of chloroform (4.7 x M) and across a

wavelength range of 200 to 800 nm.

Circular Dichroism Spectrum

300 400 500 600

wavelength (nm)

Figure 9.2.1. Circular dichroism spectrum of the CuC124igand (+)-333 complex.

BIBLIOGRAPHY

(1) Marckwald, W. Asymmetric Synthesis. Ber. Dtsh. Chem. Ges. 1904, 37, 1368.

(2) (a) Gardner, M. In The New Ambidextrous Universe, 3rd ed., W. H. Freeman & Co.,

New York, 1990. (b) Heilbromer, E.; Dunitz, J. D. In Reflections on Symmetry, VHCA,

Basel, 1993. (c) Hoffmann, R. In The Same and Not the Same, Columbia University

Press, New York, 1995.

(3) Pasteur, L. Ann. Chim. Phys. 1848,24,442.

(4) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W.-H.;

Hawkins, L. D.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W.;

Mizuno, M.; Nakata, M.; Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda,

K.; Uenishi, J.; White, J. B.; Yonaga, M. Total Synthesis of Palytoxin Carboxylic Acid

and Palytoxin Amide. J. Am. Chem. Soc. 1989, 111, 7530. (b) Suh, E. M.; Kishi, Y.

Synthesis of Palytoxin from Palytoxin Carboxylic Acid. J. Am. Chem. Soc. 1994, 116,

11205.

(5) Agranat, I.; Caner, H.; Caldwell, J. Putting Chirality to Work: The Strategy of Chiral

Switches. Nut. Rev. Drug Discovery 2002,1,753.

(6) Fischer, E. Dtsh. Chem. Ges. 1894,27, 3189.

(7) Cram, D. J.; Abd Elhafez, F. A. Studies in Stereochemistry. The Rule of "Steric

Control of Asymmetric Induction" in the Syntheses of Acyclic Systems. J. Am. Chem.

SOC. 1952, 74,5828.

(8) Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective Aldol Condensations. 2.

Erythro-selective Chiral Aldol Condensations via Boron Enolates. J. Am. Chem. Soc.

1981,103,2 127.

(9) Brown, H. C.; Zweifel, G. A Stereospecific Double Bond Hydration of the Double

Bond in Cyclic Systems. J. Am. Chem. Soc. 1959,81,247.

(10) Verbit, L.; Heffron, P. J. Optically Active sec-Butylamine via Hydroboration. J

Org. Chem. 1967,32,3 199.

(1 1) Pizzarello, S.; Weber, A. L. Prebiotic Amino Acids as Asymmetric Catalysts.

Science 2004,303, 1 15 1.

(12) Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Asymmetric Induction in Carbenoid

Reaction by means of a Dissymetric Copper Chelate. Tetrahedron Lett. 1966, 43, 5239.

(13) Dang, T. P.; Kagan, H. B. The Asymmetric Synthesis of Hydratropic Acid and

Amino-Acids by Homogenous Catalytic Hydrogenation. J. Chem. Soc., Chem. Commun.

l97l ,48 1.

(14) Whitesell, J. K. C2-Symmetry and Asymmetric Induction. Chem. Rev. 1989, 89,

1581.

(15) Knowles, W. S. Asymmetric Hydrogenation. Acc. Chem. Res. 1983,16, 106.

(16) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R.

Synthesis of 2,2'-bis(Dipheny1phosphino)- 1 , 1 '-binapthyl (BINAP), an Atropisomeric

Chiral bis(Triaryl)phosphine, and its use in the Rhodium(1)-Catalyzed Asymmetric

Hydrogenation of Alpha-(acy1amino)acrylic Acids. J. Am. Chem. Soc. 1980, 102, 7932.

(17) (a) Ohta, T.; Takaya, H.; Noyori, R. Asymmetric Hydrogenation of Unsaturated

Carboxylic Acids Catalyzed by BINAP-Ruthenium(I1) Complexes. J. Org. Chem. 1987,

52, 3 174. (b) Kitamura, M.; Yoshimura, M.; Tsukamoto, M.; Noyori, R. Synthesis of a-

Amino Phosphonic Acids by Asymmetric Hydrogenation. Enantiomer 1996,1,28 1.

(18) Katsuki, T.; Sharpless, K. B. The First Practical Method for Asymmetric

Epoxidation. J. Am. Chem. Soc. 1980,102,5974.

(19) Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Epoxidation of Allylic

Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New

York, 2000, Chapter 6A.

(20) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. Asymmetric Epoxidation Provides

Shortest Routes to Four Chiral Epoxy Alcohols which are Key Intermediates in Syntheses

of Methymycin, Erythromycin, Leukotriene C- 1 and Disparlure. J. Am. Chem. Soc. 1981,

103,464.

(21) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic Asymmetric

Dihydroxylation. Chem Rev. 1994, 94, 2483.

(22) Sharpless, K. B. Searching for New Reactivity (Nobel Lecture). Angew. Chem., Int.

Ed. 2002, 41,2024.

(23) Noyori, R. Asymmetric Catalysis: Science and Opportunities (Nobel Lecture).

Angew. Chem., Int. Ed. 2002,41,2008.

(24) Knowles, W. S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem., Int.

Ed. 2002, 41, 1998.

(25) Fritschi, H.; Leutenegger, U.; Siegrnann, K.; Pfaltz, A. Synthesis of Chiral

Semicorrin Ligands and General Concepts. Helv. Chim. Acta 1988, 71, 154 1.

(26) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Enantioselective Cyclopropane Formation

from Olefins with Diazo Compounds Catalyzed by Chiral (Semicorrinato)copper

Complexes. Helv. Chim. Acta. 1988, 71, 1553.

(27) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Asymmetric Catalytic

Cyclopropanation of Olefins: bis-Oxazoline Copper Complexes. Tetrahedron Lett. 1990,

31, 6005. (b) Lowenthal, R. E.; Masamune, S. Asymmetric Copper-Catalyzed

Cyclopropanation of Trisubstituted and Unsymmetrical cis-1,2-Disubstituted Olefins:

Modified bis-Oxazoline Ligands. Tetrahedron Lett. 1991,32, 7373.

(28) Evans, D. A.; Woerpel, K. A.; Hinman, M. M. bis(0xazolines) as Chiral Ligands in

Metal-Catalyzed Asymmetric Reactions. Catalytic Asymmetric Cyclopropanation of

Olefins. J. Am. Chem. Soc. 1991,113,726.

(29) Corey, E. J.; Imai, N.; Zhang, H.-Y. Designed Catalyst for Enantioselective Diels-

Alder Addition from a C2-Symmetric Chiral bis(Oxazo1ine)-Iron(II1) Complex. J. Am.

Chem. Soc. 1991,113,729.

(30) (a) Pfaltz, A. Chiral Semicorrins and Related Nitrogen Heterocycles as Ligands in

Asymmetric Catalysis. Acc. Chem. Res. 1993, 26, 339. (b) Johnson, J. S.; Evans, D. A.

Chiral bis(Oxazo1ine) Copper(I1) Complexes: Versatile Catalysts for Enantioselective

Cycloaddition, Aldol, Michael and Carbonyl Ene Reactions. Acc. Chem. Res. 2000, 33,

325.

(31) Taylor, M. S.; Jacobsen, E. N. Asymmetric Catalysis in Complex Target Synthesis.

Proc. Nat. Acad. Sci. 2004, 101, 5368.

(32) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. Cationic bis(Oxazoline)Cu(II) Lewis

Acid Catalysts. Applications to the Asymmetric Synthesis of ent-A'-

Tetrahydrocannabinol. Tetrahedron Lett. 1997,38, 3 193.

(33) (a) Trost, B. M. Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org.

Chem. 2004, 69, 5813. (b) Trost, B. M. Asymmetric Transition Metal-Catalyzed Allylic

Alkylations. Chem. Rev. 1996,96, 395.

(34) Trost, B. M.; Bunt, R. C. Asymmetric Induction in Allylic Alkylations of 3-

(Acyloxy)cyclopentenes. J. Am. Chem. Soc. 1994, 116,4089.

(35) (a) Dalko, P. I.; Moisan, L. In the Golden Age of Organocatalysis. Angew. Chem.,

Int. Ed. 2004, 43, 5 138. (b) Special Issue: Asymmetric Organocatalysis. Acc. Chem. Res.

2004,37, pp 487-63 1.

(36) Hajos, Z. G.; Parrish, D. R. Asymmetric Synthesis of Bicyclic Intermediates of

Natural Product Chemistry. J. Org. Chem. 1974, 39, 161 5.

(37) (a) Cannizzaro, C. E.; Houk, K. N. Magnitudes and Chemical Consequences of

R~N+-C-H--O=C Hydrogen Bonding. J. Am. Chem. Soc. 2002, 124, 7163. (b)

Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. Quantum Mechanical Predictions of

the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions.

J. Am. Chem. Soc. 2003,125,2475.

(38) (a) Cordova, A.; Notz, W.; Barbas 111, C. F. Direct Organocatalytic Aldol Reactions

in Buffered Aqueous Media. Chem. Commun. 2002, 3024. (b) Cordova, A.; Notz, W.;

Barbas 111, C. F. Proline-Catalyzed One-Step Asymmetric Synthesis of 5-Hydroxy-(2E)-

hexenal from Acetaldehyde. J. Org. Chem. 2002, 67, 30 1.

(39) Cbrdova, A. The Direct Catalytic Asymmetric Mannich Reaction. Acc. Chem. Res.

2004, 37, 102. (b) List, B. The Direct Catalytic Asymmetric Three-Component Mannich

Reaction. J. Am. Chem. Soc. 2000, 122, 9336. (c) List, B.; Pojarliev. P.; Biller, W. T.;

Martin, H. J. The Proline-Catalyzed Direct Asymmetric Three-Component Mannich

Reaction: Scope, Optimization and Application to the Highly Enantioselective Synthesis

of 1,2-Aminoalcohols. J. Am. Chem. Soc. 2002, 124, 827.

(40) (a) List, B. Direct Catalytic Asymmetric a-Amination of Aldehydes. J. Am. Chem.

Soc. 2002, 124, 5656. (b) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.;

Jmgensen, K. A. Direct L-Proline Catalyzed Asymmetric a-Amination of Ketones. J. Am.

Chem. Soc. 2002, 124,6254.

(41) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas 111, C. F. Amino Acid Catalyzed Direct

Asymmetric Aldol Reactions: A Bioorganic Approach to Catalytic Asymmetric Carbon-

Carbon Bond Forming Reactions. J. Am. Chem. Soc. 2001, 123, 5260. (b) Betancort, J.

M.; Barbas 111, C. F. Catalytic Direct Asymmetric Michael Reactions: Taming Naked

Aldehyde Donors. Org. Lett. 2001, 3, 3737.

(42) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New Strategies for Organic

Synthesis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction. J.

Am. Chem. Soc. 2000,122,4243.

(43) Paras, N. A.; MacMillan, D. W. C. New Strategies in Organic Catalysis: The First

Asymmetric Organocatalytic Friedel-Crafts Alkylation. J. Am. Chem. Soc. 2001, 123,

4370.

(44) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. The First Enantioselective

Organocatalytic Mukaiyama-Michael Reaction: A Direct Method for the Synthesis of

Enantioenriched y-Butenolide Architecture. J. Am. Chem. Soc. 2003,125, 1192.

(45) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. The Direct Enantioselective

Organocatalytic a-Chlorination of Aldehydes. J. Am. Chem. Soc. 2004,126,4 108.

(46) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. Enantioselective Organocatalytic

Hydride Reduction. J. Am. Chem. Soc. 2005,12 7,32.

(47) (a) Alibis, R.; Busqu&, F.; de March P.; Figueredo, M.; Font, J.; Gambino, M. E.;

Keay, B. A. Acetals of y-0x0-a$-unsaturated Esters in Nitrone Cycloadditions. Regio-

and Stereo-chemical Implications. Tetrahedron: Asymmetry 2001, 12, 1747. (b) Cossy J.;

BouzBouz, S. A Short Access to (+)-Ptilocaulin. Tetrahedron Lett. 1996, 37, 5091. (c)

Alexakis, A.; Mangeney, P. Chiral Acetals in Asymmetric Synthesis. Tetrahedron:

Asymmetry 1990,1,477.

(48) (a) Seebach, D.; Beck, A. K.; Heckel, A. TADDOLs, Their Derivatives, and

TADDOL Analogues: Versatile Chiral Auxiliaries. Angew. Chem., Int. Ed. 2001, 40, 92.

(b) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, H. W.

M.; Reynolds, D. J. 1,2-Diacetals: A New Opportunity for Organic Synthesis. Chem. Rev.

2001,101, 53.

(49) Johnson, W. S. Biomimetic Polyene Cyclizations. Angew. Chem., Int. Ed. 1976, 15,

9.

(50) Tamura, Y.; Kondo, H.; Annoura, H.; Takeuchi, R.; Fujioka, F. Diastereoselective

Nucleophilic Addition to Chiral Open-Chain a-Ketoacetals: Synthesis of (R)- and (S)-

Mevalolactone. Tetrahedron Lett. 1986,27,2 1 17.

(51) Mulzer, J.; Altenback, H.-J.; Braun, M.; Krohn, K.; Reissig, H.-U. In Organic

Synthesis Highlights, Wiley-VCH, Weinheim, 199 1, p 19.

(52) Narine, A. A.; Wilson, P. D. Synthesis and Evaluation of 7-Hydroxyindan-l-one-

Derived Chiral Auxiliaries. Can J. Chem. 2005,83,4 13.

(53) Narine, A. A. Design, Synthesis and Evaluation of Chiral Auxiliaries, Ligands and

Catalysts for Asymmetric Synthesis. Ph. D. Thesis, Simon Fraser University, 2004.

(54) McWhinnie, W. R.; Poller, R. C.; Thevarasa, M. An Inclusion Compound from

Hexaphenylditin and Tetraphenylditin. J. Organomet. Chem. 1968, 11,499.

(55) (a) Malkov, A. V.; KoEovsky, P. Chiral Bipyridine Derivatives in Asymmetric

Catalysis. Curr. Org. Chem. 2003, 7, 1737. (b) Chelucci, G.; Thummel, R. P. Chiral

2,2'-Bipyridines, 1 , 1 0-Phenanthrolines, and 2,2':6',2 "-Terpyridines: Synthesis and

Applications in Asymmetric Homogenous Catalysis. Chem. Rev. 2002, 102, 3 129. (c)

Fletcher, N. C. Chiral2,2-Bipyridines: Ligands for Asymmetric Induction. J. Chem. Soc.,

Perkin Trans. 1 2002, 183 1.

(56) (a) Reedijk, J. In Comprehensive Coordination Chemistry; Wilkinson, G., Gillard, R.

D., McCleverty, J. A., Eds; Pergamon Press: Oxford, 1987; Vol. 2, pp 73-98. (b) Kaes,

C.; Katz, A.; Hosseini, M. W. Bipyridine: The Most Widely Used Ligand. A Review of

Molecules Containing at Least Two 2,2'-Bipyridine Units. Chem. Rev. 2000, 100,3553.

(57) Johnson, J. S.; Evans, D. A. Chiral bis(Oxazo1ine) Copper(I1) Complexes: Versatile

Catalysts for Enantioselective Cycloaddition, Aldol, Michael and Carbonyl Ene

Reactions. Acc. Chem. Res. 2000, 33, 325.

(58) Bolm, C.; Zehnder, M.; Bur, D. Optically Active Bipyridines in Asymmetric

Synthesis. Angew. Chem., Int. Ed. 1990,29,205.

(59) Krohnke, F. Neuere Methoden der Praparativen Organischen Chemie Synthesen mit

hilfe von Pyridiniumsalzen. Angew. Chem., Int. Ed. 1963,2, 386.

(60) Hayoz, P.; von Zelewsky, A. New Versatile Optically Active Bipyridines as

Building Blocks for Helicating and Caging Ligands. Tetrahedron Lett. 1992, 33, 5165.

(61) Ito, K.; Tabuchi, S.; Katsuki, T. Synthesis of New Chiral Bipyridine Ligands and

Their Application to Asymmetric Cyclopropanation. Synlett 1992, 575.

(62) Ito, K.; Katsuki, T. Synthesis of New Chiral Bipyridine Ligands and Their

Application to Asymmetric Cyclopropanation. Chem. Lett. 1994, 1857.

(63) Ito, K.; Yoshitake, M.; Katsuki, T. Chiral Bipyridine and Biquinoline Ligands: Their

Asymmetric Synthesis and Application to the Synthesis of trans-Whisky Lactone.

Tetrahedron 1996, 52, 3905.

(64) Fukuda, T.; Irie, R.; Katsuki, T. Mn-Salen Catalyzed Asymmetric Epoxidation of

Conjugated Trisubstituted Olefins. Synlett 1995, 197.

(65) Malkov, A. V.; Bella, M.; Langer, V.; KoEovsky, P. PINDY: A Novel, Pinene-

Derived Bipyridine and its Application in Asymmetric, Copper(1)-Catalyzed Allylic

Oxidation. Org. Lett. 2000,2, 3047.

(66) Chelucci, G.; Saba, A. New Synthetic Route to C2-Symmetric 2,2'-Bipyridines:

Synthesis of (6R,6'R,8R,8R')-6,8,6',8'-Bismethano-7,7,7',7'-tetramethyl-5,5',6,6',7,7'-

octahydro-2,2 '-biquinoline. Synth. Commun. 2001, 3 l , 3 16 1.

(67) (a) Noyori, R. Centenary Lecture. Chemical Multiplication of Chirality: Science and

Applications. Chem. Soc. Rev. 1989, 18, 187. (b) Pu, L. 1,1 '-Binapthyl Dimers,

Oligomers, and Polymers: Molecular Recognition, Asymmetric Catalysis and New

Materials. Chem. Rev. 1998,98,2405.

(68) Noyori, R. BINAP: An Efficient Chiral Element for Asymmetric Catalysis. Acc.

Chem. Res. 1990,23,345.

(69) Wang, X. C.; Cui, Y. X.; Mak, T. C. W.; Wong, H. N. C. Synthesis, Metal Complex

Formation, and Resolution of a New C2 Diazabiaryl Ligand: Cyclo-octa[2,1-b:3,4-

b'ldipyridine. J. Chem. Soc., Chem. Commun. 1990, 167.

(70) Botteghi, C.; Schionato, A.; De Lucchi, 0. A C2-Symmetric Chiral 2,2'-Bipyridine

Derived From Tartaric Acid. Synth. Commun. 1991,21, 1819.

(71) Wong, H. L.; Tian, Y.; Chan, K. S. Electronically Controlled Asymmetric

Cyclopropanation Catalyzed by a New Type of Chiral2,2'-Bipyridine. Tetrahedron Lett.

2000,41,7723.

(72) Worsdorfer, E.; Vogtle, F.; Nieger, M.; Waletzke, M.; Grimme, S.; Glorius, F.;

Pfaltz, A. A New Planar Chiral Bipyridine Ligand. Synthesis 1999, 597.

(73) Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C. Synthesis, Resolution and

Crystallographic Characterization of a New C2-Symmetric Planar-Chiral Bipyridine

Ligand: Application to the Catalytic Enantioselective Cyclopropanation of Olefins.

Chem. Commun. 2000,377.

(74) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic

Synthesis with Diazo Compounds; J . Wiley: New York, 1998.

(75) (a) Doyle, M. P.; Forbes, D. C. Recent Advances in Asymmetric Catalytic Metal

Carbene Transformations. Chem. Rev. 1998, 98, 91 1. (b) Doyle, M. P.; Protopopova, M.

N. New Aspects of Catalytic Asymmetric Cyclopropanation. Tetrahedron 1998, 54,

7919.

(76) (a) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Asymmetric Synthesis of Chrysanthemic

Acid. An Application of Copper Carbenoid Reaction. Tetrahedron Lett. 1975, 1707. (b)

Aratani, T.; Yoneyoshi, Y.; Nagase, T. Asymmetric Synthesis of Permethric Acid.

Stereochemistry of Chiral Copper Carbenoid Reaction. Tetrahedron Lett. 1982, 23, 685.

(c) Aratani, T. Catalytic Asymmetric-Synthesis of Cyclopropane-Carboxylic Acids - An

Application of Chiral Copper Carbenoid Reaction. Pure Appl. Chem. 1985, 57, 1839.

(77) Doyle, M. P. Catalytic Methods for Metal Carbene Transformations. Chem. Rev.

1986, 86, 919.

(78) Doyle, M. P. Metal Carbene Complexes in Organic Synthesis: Diazodecomposition-

Insertion and Ylide Chemistry. In Comprehensive Organometallic Chemistry II;

Hegedus, L. S., Ed.; Pergamon Press; New York, 1995; Vol. 12, Chapter 5.2.

(79) Salomon, R. G.; Kochi, J. K. Copper(1) Catalysis in Cyclopropanations with Diazo

Compounds. The Role of Olefin Coordination. J. Am. Chem. Soc. 1973,95,3300.

(80) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Semicorrin Metal Complexes as

Enantioselective Catalysts. Part 2. Enantioselective Cyclopropane Formation from

Olefins with Diazo Compounds Catalyzed by Chiral (Semicorrinato)copper Complexes.

Helv. Chim. Acta. 1988, 71, 1553.

(81) Lowenthal, R. E.; Abiko, A.; Masamune, S. Asymmetric Catalytic Cyclopropanation

of Olefins: bis(Oxazo1ine) Copper Complexes. Tetrahedron Lett. 1990, 31,6005.

(82) Kwong, H.-L.; Lee, W .-S.; Ng, H.-F.; Chiu, W.-H.; Wong, W.-T. Chiral Bipyridine-

Copper(I1) Complex. Crystal Structure and Catalytic Activity in Asymmetric

Cyclopropanation. J. Chem. Soc., Dalton Trans. 1998, 1043.

(83) Kharasch, M. S.; Sosnovsky, G.; Yang, N. C. Reactions of tert-Butyl Peresters I.

The Reaction of Peresters With Olefins. J. Am. Chem. Soc. 1959, 81, 58 19.

(84) Andrus, M. B.; Chen, X. Catalytic Enantioselective Allylic Oxidation of Olefins

with Copper(1) Catalysts and New Perester Oxidants. Tetrahedron 1997, 53, 16229.

(85) Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A. Enantioselective Allylic Oxidation

Catalyzed by Chiral bis(Oxazo1ine)-Copper Complexes. Tetrahedron Lett. 1995, 36,

1831.

(86) Andrus, M. B.; Argade, A. B.; Chen, X.; Pamment, M. G. The Asymmetric

Kharasch Reaction. Catalytic Enantioselective Allylic Acyloxylation of Olefins with

Chiral Copper(1) Complexes and tert-Butyl Perbenzoate. Tetrahedron Lett. 1995, 36,

2945.

(87) Hayes, R.; Wallace, T. W. A Simple Route to Methyl (5s)-Benzoyloxy-6-

oxohexanoate, a Key Intermediate in Leukotriene Synthesis. Tetrahedron Lett. 1990, 31,

3355.

(88) Andrus, M. B.; Zhou, Z. Highly Enantioselective Copper-bisoxazoline-Catalyzed

Allylic Oxidation of Cyclic Olefins with tert-Butyl p-Nitroperbenzoate. J. Am. Chem.

Soc. 2002,124,8806.

(89) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;

KoEovsk?, P. Chiral 2,2'-Bipyridine-Type N-Monoxides as Organocatalysts in the

Enantioselective Allylation of Aldehydes with Allyltrichlorosilane. Org. Lett. 2002, 4,

1047.

(90) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. A Novel Axially Chiral 2,2'-

Bipyridine NJV-Dioxide. Its Preparation and use for Asymmetric Allylation of

Aldehydes with Allyl(trichloro)silane as a Highly Efficient Catalyst. Org. Lett. 2002, 4,

2799.

(91) Denmark, S. E.; Fan, Y. Catalytic, Enantioselective Aldol Additions to Ketones. J.

Am. Chem. Soc. 2002,124,4233.

(92) Chelucci, G.; On+, G.; Pinna, G. A. Chiral Pa-Ligands with Pyridine-Nitrogen and

Phosphorus Donor Atoms. Syntheses and Applications in Asymmetric Catalysis.

Tetrahedron 2003,59,947 1.

(93) Helmchen, G.; Pfaltz, A. Phosphinooxazolines - A New Class of Versatile, Modular

Pa-Ligands for Asymmetric Catalysis. Acc. Chem. Res. 2000,33,336.

(94) Chelucci, G.; Cabras, M. A.; Botteghi, C.; Basoli, C.; Marchetti, M. Synthesis of

Homochiral Pyridyl, Bipyridyl and Phosphino Derivatives of 2,2-Dimethyl- 1,3-

dioxolane: Use in Asymmetric Catalysis. Tetrahedron: Asymmetty 1996, 7, 885

(95) Varela, J. A.; Saa, C. Construction of Pyridine Rings by Metal-Mediated [2+2+2]

Cycloaddition. Chem. Rev. 2003,103,3787.

(96) Ito, K.; Kashiwagi, R.; Iwasaki, K.; Katsuki, T. Asymmetric Allylic Alkylation using

a Palladium Complex of Chiral 2-(Phosphinoary1)pyridine Ligands. Synlett 1999, 10,

1563.

(97) Malkov, A. V.; Bella, M.; Stara, G.; KoEovsky, P. Modular Pyridine-Type P,N-

Ligands Derived from Monoterpenes: Application in Asymmetric Heck Addition.

Tetrahedron Lett. 2001, 42, 3045.

(98) Chelucci, G.; Saba, A.; Soccolini, F. Chiral2-(2-Diphenylphosphinopheny1)-5,6,7,8-

tetrahydroquinolines: New P,N-Ligands for Asymmetric Catalysis. Tetrahedron 2001,

57,9989.

(99) (a) Dai, X.; Wong, A.; Virgil, S. Synthesis and Resolution of Quinazolinone

Atropisomeric Phosphine Ligands. J. Org. Chem, 1998, 63, 2597. (b) Dai, X.; Virgil, S.

Asymmetric Allylic Alkylation by Palladium Complexes with Atropisomeric

Quinazolinone Phosphine Ligands. Tetrahedron Lett. 1999, 40, 1245.

(100) Hu, W.; Chen, C.-C.; Zhang, X. Development of New Chiral P,N Ligands and

Their Application in the Cu-Catalyzed Conjugate Addition of Diethylzinc to Enones.

Angew. Chem., Int. Ed. 1999,38, 35 1 8.

(101) Tao, B.; Fu, G. C. Application of a New Family of P,N-Ligands to the Highly

Enantioselective Hydrosilylation of Aryl Alkyl and Dialkyl Ketones. Angew. Chem., Int.

Ed. 2002, 41,3892.

(102) (a) Trost, B. M. Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org.

Chem. 2004, 69, 5813. (b) Trost, B. M. Pd Asymmetric Allylic Alkylation (AAA). A

Powerful Synthetic Tool. Chem. Pharm. Bull. 2002, 50, 1. (c) Trost, B. M.; Van

Vranken, D. L. Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev.

1996, 96, 395.

(103) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic

Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921.

(104) Moberg, C.; Brember, U.; Hallman, K.; Svensson, M.; Norrby, P.; Hallberg, A.;

Larhed, M.; Csoregh, I. Selectivity and Reactivity in Asymmetric Allylic Alkylation.

Pure Appl. Chem. 1999, 71, 1477.

(105) Sauthier, N.; Fornies, J.; Toupet, L.; Reau, R. Palladium(I1) Complexes of Chiral

1,2-Diiminophosphoranes: Synthesis, Structural Characterization, and Catalytic Activity

for the Allylic Alkylation. Organometallics 2000, 19, 553.

(106) Trost, B. M.; Toste, F. D. Regio- and Enantioselective Allylic Alkylation of an

Unsymmetrical Substrate: A Working Model. J. Am. Chem. Soc. 1999,121,4545.

(107) Trost, B. M.; Murphy, D. J. A Model for Metal-Templated Catalytic Asymmetric

Synthesis via n-Ally1 Fragments. Organometallics 1985,4, 1 143.

(108) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Asymmetric Heck Reaction. Adv. Synth.

Catal. 2004,346, 1533.

(109) Sato, Y.; Sodeoka, ,M.; Shibasaki, M. Catalytic Asymmetric Carbon-Carbon Bond

Formation: Asymmetric Synthesis of cis-Decalin Derivatives by Palladium-Catalyzed

Cyclization of Prochiral Alkenyl Iodides. J. Org. Chem. 1989, 54, 4738.

(1 10) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. Palladium-Catalyzed Polyene

Cyclizations of Trienyl Triflates. J. Org. Chem. 1989, 54, 5846.

(1 11) Loiseleur, 0. ; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz, A. J. Organomet.

Chem. 1999,576, 16.

(112) Sharpless, K.; Amberg, Y.; Bannani, G.; Crispino, J.; Hartung, K.; Jeong, H.;

Kwong, K.; Morikawa, Z.; Wang, D. Xu, X.; Zhang, X.-L. The Osmium-Catalyzed

Asymmetric Dihydroxylation: A New Ligand Class and a Process Improvement. J. Org.

Chem. 1992,57,2768.

(1 13) Prasad, K. R. K.; Joshi, N. N. Stereoselective Reduction of Benzils: A New

Convenient Route to Enantiomerically Pure 1,2-Diarylethanediols. J. Org. Chem. 1996,

61, 3888.

(114) (a) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. Enantioselective

Complexation of Organic Ammonium Ions By Simple Tetracyclic Podand Ionophores. J.

Am. Chem. Soc. 1992, 114, 4128. (b) Matteson, D. S.; Beedle, E. C.; Kandil, A. A.

Preparation of (3S,4$)-2,5-Dimethy1-3,4-hexane Diol [(S)-DIPED] from (R,R)-Tartaric

Acid via Trimethylsilyl Chloride Catalyzed Acetylation of a Hindered 1,4-Diol. J. Org.

Chem. 1987,52,5034.

(1 15) Sakurai, A.; Midorikawa, H. The Cyclization of Ethyl Acetoacetate and Ketones by

Ammonium Acetate. Bull. Chem. Soc. Jpn. 1968,41, 165.

(1 16) Ruble, J. C.; Fu, G. C. Chiral n-Complexes of Heterocycles with Transition Metals:

A Versatile New Family of Nucleophilic Catalysts. J. Org. Chem. 1996, 61, 7230.

(1 17) Robison, M. M. The Preparation of 1,5-Pyrindene. J. Am. Chem. Soc. 1958, 80,

6254.

(118) Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C. Synthesis, Resolution and

Crystallographic Characterication of a New Cz-Symmetric Planar-Chiral Bipyridine

Ligand: Application to the Catalytic Enantioselective Cyclopropanation of Olefins.

Chem. Commun. 2000,377.

(1 19) Mancuso, A. J.; Huang, S. L.; Swern, D. Oxidation of Long Chain and Related

Alcohols to Carbonyls by Dimethyl Sulfoxide "Activated" by Oxalyl Chloride. J. Org.

Chem. 1978,43,2480.

(120) (a) Katada, M. J. Pharm. Soc. Jpn. 1947, 67, 51. (b) Boekelheide, V.; Linn, W. J.

Rearrangements of N-Oxides. A Novel Synthesis of Pyridyl Carbinols and Aldehydes. J.

Am. Chem. Soc. 1954, 76, 1286.

(121) Oae, S.; Tamagaki, S.; Negoro, T.; Ogino, K.; Kozuka, S. Kinetic Studies on the

Reactions of 2- and 4-Alkyl-Substituted Heteroaromatic N-Oxides with Acetic

Anhydride. Tetrahedron Lett. 1968,9 17.

(122) (a) Dehmlow, E. V.; Sleegers, A. Synthesis of Unsymmetrically and Symmetrically

Structured Dihydroxybipyridines. Liebigs Ann. Chem. 1992, 953. (b) Iyoda, M.; Otsuka,

H.; Sato, K.; Nisato, N.; Oda, M. Homocoupling of Aryl Halides using Nickel(I1)

Complex and Zinc in the Presence of Et4NI. An Efficient Method for the Synthesis of

Biaryls and Bipyridines. Bull. Chem. Soc. Jpn. 1990, 63, 80.

(123) Grushin, V. V.; Alper, H. Transformation of Chloroarenes, Catalyzed by

Transition-Metal Complexes. Chem. Rev. 1994, 94, 1047.

(124) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and Organometallic

Compounds; Academic Press: London, 1970.

(125) Milstein, D.; Stille, J. K. A General, Selective and Fascile Method for Ketone

Synthesis from Acid Chlorides and Organotin Compounds Catalyzed by Palladium. J.

Am. Chem. Soc. 1978,100,3636.

(126) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (b)

Mitchell, T. N. In Metal Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,

Eds.; Wiley-VCH: New York, 1998; Chapter 4.

(127) Echavarren, A. M.; Stille, J. K. Palladium-Catalyzed Coupling of Aryltriflates with

Organostannanes. J. Am. Chem. Soc. 1987,109,5478.

(128) Littke, A. F.; Schwarz, L.; Fu, G. C. pd/P(t-B~)~: A Mild and General Catalyst for

Stille Reactions of Aryl Chlorides and Aryl Bromides. J. Am. Chem. Soc. 2002, 124,

6343.

(129) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teplf, F.; Meghani,

P.; KoCovskf, P. Synthesis of New Chiral2,2'-Bipyridyl Ligands and their Application in

Copper-Catalyzed Asymmetric Allylic Oxidation and Cyclopropanation. J. Org. Chem.

2003,68,4727.

(130) Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A. Semicorrin Metal

Complexes as Enantioselective Catalysts. Helv. Chim. Acta 1988, 71, 1541.

(131) Niimi, T.; Uchida, T.; hie, R.; Katsuki, T. Highly Enantioselective

Cyclopropanation with Co(1I)-Salen Complexes: Control of cis- and trans-Selectivity by

Rational Ligand Design. Adv. Synth. Catal. 2001, 343, 79.

(132) Hopf, H. In Classics in Hydrocarbon Chemistry; Wiley-VCH: Weinheim, 2000; pp

321-368.

(133) Lipshutz, B. H.; Tomioka, T.; Pfeiffer, S. S. Mild and Selective Reductions of Aryl

Halides Catalyzed by Low-Valent Nickel Complexes. Tetrahedron Lett. 2001,42, 7737.

(134) Silverstein, R. M.; Webster, F. X. Infrared Spectrometry. In Spectrometric

IdentzJication of Organic Compounds, 6th ed.; John Wiley & Sons, Inc. New York, 1998;

Chapter 3.

(135) (a) Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, H. Enantioselective Ring-

Opening of meso-Epoxides with Tetrachlorosilane Catalyzed by Chiral Bipyridine N,N'-

Dioxide Derivatives. Tetrahedron Lett. 2002, 43, 8827. (b) Garrett, C. E.; Fu, G. C. IT-

Bound Phosphorus Heterocycles as Catalysts: Ring-Opening of Expoxides with TMSCl

in the Presence of a Phosphaferrocene. J. Org. Chem. 1997, 62, 4534. (c) Denmark, S.

E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. Enantioselective Ring-Opening of

Epoxides with Silicon Tetrachloride in the Presence of a Chiral Lewis Base. J. Org.

Chem. 1998,63,2428.

(136) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross Coupling Reactions of

Organoboron Compounds. Chem. Rev. 1995,95,2457.

(137) Littke, A. F.; Dai, C.; Fu, G. C. Versatile Catalysts for the Suzuki Cross-Coupling

of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions.

J. Am. Chem. Soc. 2000,122,4020.

(138) Kiindig, E. P.; Meier, P. Synthesis of New Chiral Bidentate

(Phosphinophenyl)benzooxazine P,N-Ligands. Helv. Chim. Actu 1999,82, 1360.

(139) (a) Draper, N. D.; Batchelor, R. J.; Leznoff, D. B. Tuning the Structures of Mercury

Cyanide-Based Coordination Polymers with Transition Metal Cations. Cvstal Growth

and Design 2004, 4, 621. (b) Haftbaradaran, F.; Draper, N. D.; Leznoff, D. B.; Williams,

V. E. A Strained Silver(1) Coordination Polymer of 1,4-Diazatriphenylene. J. Chem. Soc.,

Dalton Trans. 2003, 2105. (c) Draper, N. D.; Batchelor, R. J.; Leznoff, D. B. Using

HgX2 Units (X = CN, C1) to Increase Structural and Magnetic Dimensionality in

Conjunction with (2,2'-Bipyridyl)copper(II) Building Blocks. Polyhedron 2003, 22,

1735.

(140) Gilbertson, S. R.; Xie, D.; Fu, Z. Proline-Based PJV Ligands in Asymmetric

Allylation and the Heck Reaction. J. Org. Chem. 2001, 66, 7240.

(141) (a) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Mechanistic and Synthetic Studies in

Catalytic Allylic Alkylation with Palladium Complexes of 1-(2-Diphenylphosphino-1-

napthyl)isoquinoline. Tetrahedron 1994, 50, 4493. (b) Bovens, M.; Togni, A.; Venanzi,

L. M. Asymmetric Allylic Alkylation with Palladium Coordinated to a New Optically

Active Pyrazolylmethane Ligand. J. Organomet. Chem. 1993,451, C28.

(142) Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K.

Asymmetric Synthesis Catalyzed by Chiral Ferrocenylphosphine-Transition-Metal

Complexes. Palladium Catalyzed Asymmetric Allylic Amination. J. Am. Chem. Soc.

1989,111,6301.

(143) (a) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. Asymmetric Synthesis.

Asymmetric Catalytic Allylation using Palladium Chiral Phosphine Complexes. J. Am.

Chem. Soc. 1985, 107, 2033. (b) Mackenzie, P. B.; Whelan, J.; Bosnich, B. Asymmetric

Synthesis. Mechanism of Asymmetric Catalytic Allylation. J. Am. Chem. Soc. 1985, 107,

2046.

(144) Gilbertson, S. R.; Lan, P. Kinetic Resolution in Palladium-Catalyzed Asymmetric

Allylic Alkylations by a P,O Ligand System. Org. Lett. 2001, 3, 2237.

(145) (a) Mancherio, 0. G.; Priego, J.; Rambn, S. C.; Arrayas, R. G.; Liamas, T.;

Carretero, C. 1-Phosphino-2-sulfenylferrocenes as Planar Chiral Ligands in

Enantioselective Palladium-Catalyzed Allylic Substitutions. J. Org. Chem. 2003, 68,

3679. (b) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagni, M. R.

Application of Chiral Mixed Phosphorus/Sulfur Ligands to Palladium-Catalyzed Allylic

Substitutions. J. Am. Chem. Soc. 2000,122,7905.

(146) Seeman, J. I. Effect of Conformational Change on Reactivity in Organic Chemistry.

Evaluations, Applications, and Extensions of Curtin-Hammett Winstein-Holness

Kinetics. Chern. Rev. 1983,83, 83.

(1 47) Gold, V. Glossary of Terms used in Physical Organic Chemistry. Pure Appl. Chem.

1979,51,1725.

(148) (a) Helmchen, G.; Pfaltz, A. Phosphinooxazolines - A New Class of Versatile,

Modular Pa-Ligands for Asymmetric Catalysis. Acc. Chem. Res. 2000, 33, 336. (b)

Pfaltz, A.; Drury 111, W. J. Design of Chiral Ligands for Asymmetric Catalysis. From C2-

Symmetric P,P and N,N-Ligands to Sterically and Electronically Nonsymmetrical P,N-

Ligands. Proc. Nat. Acad. Sci. 2004, 101,5723.

(149) Lightfoot, A.; Schnider, P.; Pfaltz, A. Enantioselective Hydrogenation of Olefins

with Iridium-Phosphanodihydrooxazole Catalysts. Angew. Chern., Int. Ed. 1998, 37,

2897.

(150) (a) Kainz, S.; Brinkmann, A.; Leitner, W.; Pfaltz, A. Iridium-Catalyzed

Enantioselective Hydrogenation of Imines in Supercritical Carbon Dioxide. J. Am. Chem.

Soc. 1999,121,6421.

(151) Jung, Y. J.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Oxygen-Promoted Pd(I1)

Catalysis for the Coupling of Organoboron Compounds and Olefins. Org. Lett. 2003, 5,

223 1.

(1 52) Vineyard, B. D.; Knowles, W. S.; Saback, M. J.; Bachman, G. L.; Weinkauff, D. J.

Asymmetric Hydrogenation. Rhodium Chiral Biphosphine Catalyst. J. Am. Chem. Soc.

1977,99,5946.

(153) Ruble, J. C.; Fu, G. C. Chiral n-Complexes of Heterocycles with Transition Metals:

A Versatile New Family of Nucleophilic Catalysts. J. Org. Chem. 1996, 61, 7230.

(154) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic Asymmetric

Dihydroxylation. Chem. Rev. 1994,94,2483.

(155) (a) Wang, Z.-M.; Kakiuchi, K.; Sharpless, K. B. Osmium-Catalyzed Asymmetric

Dihydroxylation of Cyclic cis-Disubstituted Olefins. J. Org. Chem. 1994, 59, 6895. (b)

Wang, L.; Sharpless, K. B. Catalytic Asymmetric Dihydroxylation of cis-Disubstituted

Olefins. J. Am. Chem. Soc. 1992,114,7568.

(156) Wang, Z.-M.; Sharpless, K. B. A Solid-to-Solid Asymmetric Dihydroxylation

Procedure for Kilogram-Scale Preparation of Enantiopure Hydrobenzoin. J. Org. Chem.

1994,59,8302.

(157) Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; SancCau, J.-Y.; Bennani, Y.

Asymmetric Dihydroxylation of Olefins With a Simple Chiral Ligand. J. Org. Chem.

1993,58, 199 1.

(158) Spivey, A. C.; Hanson, R.; Scorah, N.; Thorpe, S. J. Sharpless Asymmetric

Dihydroxylation: Effect of Alkene Structure on Rates and Selectivity. J. Chem. Ed. 1999,

76, 655.

(159) Hale, K. J.; Manaviazar, S.; Peak, S. A. Anomalous Enantioselectivity in the

Sharpless Catalytic Asymmetric Dihydroxylation Reaction of 1,l -Disubstituted Ally1

Alcohol Derivatives. Tetrahedron Lett. 1994,35,425.

(160) Agarwal, S. K.; Boyd, D. R.; Davies, J. H.; Hamilton, L.; Jerina, D. M.;

McCullough, J. J.; Porter, H. P. Synthesis of Arene Oxide and trans-Dihydrodiol

Metabolites of Quinoline. J. Chem. Soc., Perkin Trans. 1 1990, 1969.

(161) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.; Teplf, F.; Meghani,

P.; KoEovskf, P. Synthesis of New Chiral 2,2'-Bipyridine Ligands and their Application

in Copper-Catalyzed Asymmetric Allylic Oxidation and Cyclopropanation. J. Org.

Chem. 2003,68,4727.

(162) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Highly Enantioselective

Cyclopropanantion with Co(11)-Salen Complexes: Control of cis- and trans-Selectivity by

Rational Ligand Design. Adv. Synth. Catal. 2001, 343,79.

(163) Doyle, M. P. Chiral Catalysts for Enantioselective Carbenoid Cyclopropanation

Reactions. Recl. Trav. Chim. Pays-Bas 1991,110,305.

(164) Doyle, M. P. Asymmetric Addition and Insertion Reactions of Catalytically-

Generated Metal Carbenes. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;

Wiley-VCH: New York, 2000; Chapter 5.

(165) (a) Friedel, C.; Crafts, J. M. R. Hebd. Seances Acad. Sci. 1877, 84, 1392. (b)

Friedel, C.; Crafts, J. M. R. Hebd. Seances Acad. Sci. 1877, 84, 1450.

(166) Olah, G. A.; h s n a m u r t i , R.; Prakash, G. K. S. In Comprehensive Organic

Synthesis, lSt ed.; Pergamon: New York, 1991; Vol. 3, pp 293-339

(167) (a) Bigi, F.; Casiraghi, G.; Casnati, G.; Satori, G. Asymmetric Electrophilic

Substitution on Phenols. Enantioselective ortho-Hydroxyalkylation Mediated by Chiral

Alkoxyaluminum Chlorides. J. Org. Chem. 1985, 50, 5018. (b) Erker, G.; van der

Zeijden, A. A. H. Enantioselective Catalysis with a New Zirconium Trichloride Lewis

Acid Containing a "Dibornacyclopentadienyl" Ligand. Angew. Chem., Int. Ed. 1990, 29,

5 12.

(168) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jmgensen, K. A. Catalytic, Highly

Enantioselective Friedel-Crafts Reactions of Aromatic and Heteroaromatic Compounds

to Trifluoropyruvate. A Simple Approach for the Formation of Optically Active

Aromatic and Heteroaromatic Hydroxy Trifluoromethyl Esters. J. Org. Chem. 2001, 66,

1009. (b) Gathergood, N.; Zhuang, W.; Jmgensen, K. A. Catalytic Enantioselective

Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate: A Simple Procedure

for the Synthesis of Optically Active Mandelic Acid Esters. J. Am. Chem. Soc. 2000, 122,

12517.

(169) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jmgensen, K. A. Catalytic Asymmetric

Friedel-Crafts Alkylation of P,y-Unsaturated a-Ketoesters: Enantioselective Addition of

Aromatic C-H Bonds to Alkenes. Angew. Chem., Int. Ed. 2001,40, 160.

(170) van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.; Jsrgensen, K. A.

Formation of Optically Active Chromanes by Catalytic Asymmetric Tandem oxa-

Michael Addition-Friedel-Crafts Alkylation Reactions. Org. Biomol. Chem. 2003, 1,

1953.

(171) Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jwgensen, K. A. On the Intermediates

in Chiral bis(Oxazoline)copper(II)-Catalyzed Enantioselective Reactions-Experimental

and Theoretical Investigations. Chem. Eur. J. 2002, 8, 1888.

(172) Hanan, G. S.; Schubert, U. S.; Volkrner, D.; Riviere, E.; Lehn, J.-M.; Kyritsakas,

N.; Fischer, J. Synthesis. Structure and Properties of oligo-Tridentate Ligands:

Covalently Assembled Precursors of Coordination Arrays. Can. J. Chem. 1997, 75, 169.

(173) (a) Kobayashi, S. Scandium Triflate in Organic Synthesis. Eur. J. Org. Chem.

1999, 15. (b) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J.

Enantioselective Indole Friedel-Crafts Alkylations Catalyzed by bis(Oxazoliny1)pyridine-

Scandium(II1) Triflate Complexes. J. Am. Chem. Soc. 2003, 125, 10780. (c) Schneider,

C.; Sreekanth, A. R.; Mai, E. Scandium-Bipyridine-Catalyzed Enantioselective Addition

of Alcohols and Amines to meso-Epoxides. Angew. Chem., Int. Ed. 2004,43, 5691.

(174) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4~ ed.;

Butterworth-Heinemann: Oxford, 1997.

(175) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for

Preparative Separations with Moderate Resolution. J. Org. Chem. 1978, 43,2923.

(176) de Meulenaer, J.; Tompa, H. Acta Cryst. 1965, 19, 10 14.

(177) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.; Cooper, R. I.

CRYSTALS Issue 12.50; Chemical Crystallography Laboratory, University of Oxford,

Oxford, England, 2003.

(178) International Union of Crystallography. International Tables for X-Ray

Crystallography; Kynoch Press: Birmingham, 1952.

(179) Denmark, S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. Enantioselective

Ring Opening of Epoxides with Silicon Tetrachloride in the Presence of a Chiral Lewis

Base. J. Org. Chem. 1998, 63,2428.

(180) Kiindig, P. E.; Meier, P. Synthesis of New Chiral Bidentate

(Phosphinopheny1)benzoxazine Pfl-Ligands. Helv. Chim. Acta 1999,82, 1360.

(181) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagnk, M. R.

Application of Chiral Mixed Phosphorus/Sulfur Ligands to Palladium-Catalyzed Allylic

Substitutions. J. Am. Chem. Soc. 2000,122,7905.

(182) Gabe, E. J.; Lepage, Y.; Charland, J. P.; Lee, F. L.; White, P. S. J. Appl. Cryst.

1989,22, 384-387.

(183) Dujardin, G.; Leconte, S.; Benard, A.; Brown, E. A Straightforward Route to E-y-

Aryl-a-oxobutenoic Esters by One-step Acid-catalysed Crotonisation of Pyruvates.

Synlett 2001, 147.

Design, synthesis and evaluation of chiral nonracemic ligands and

Documents

Transcript of Design, synthesis and evaluation of chiral nonracemic ligands and